Active Agent Delivery Devices and Methods of Using the Same

ABSTRACT

Provided are active agent delivery devices configured to deliver an active agent formulation into or through a mucosal layer in a subject. The active agent delivery devices include a power reservoir configured to eject the active agent formulation at a pressure sufficient to deliver the active agent formulation into or through a mucosal layer in a subject. Methods of using the subject active agent delivery devices are also provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. § 119(e) to the filingdate of U.S. Provisional Application No. 62/057,887, filed Sep. 30,2014, the disclosure of which is incorporated herein by reference.

REFERENCE TO GOVERNMENT SUPPORT

This invention was made with government support under grant numbersHHSN268201000043C and HL096796 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

INTRODUCTION

The effort to develop needle-free active agent delivery systems throughthe non-invasive transmucosal route including but not limited to buccal,endosinusial, endotracheal, enteral, intragastric, transtracheal,auricular, intraocular, retrobulbar, conjunctival, vaginal, urogenital,anal and nasal has been a challenge due to the poor mucus permeability,leading to low active agent bioavailability and therapeutic efficacy.The low active agent bioavailability in the transmucosal route is mainlydue to the physical and biochemical barrier to absorption of the activeagent, such as large molecules including proteins and peptides, that isformed by the mucosal layer. Over the past decades several technologieshave been explored to overcome the mucus biochemical barrier, such as bydeveloping nanoparticles and liposomes to minimize enzymaticdegradation, and by attempting to increase active agent absorptionthrough the mucus physical barrier at the site of active agent releaseby developing mucoadhesives and absorption enhancers. Despite theseefforts over the past decades, non-invasive mucosal delivery remains achallenge. Thus, there is a need for a suitable delivery system foradministering active agents that can maintain the active agentintegrity, improve bioavailability and overcome the mucus barrier tofacilitate active agent absorption at the site where the active agent isreleased.

SUMMARY

The present disclosure provides active agent delivery devices, which candeliver a high-pressure jet of an active agent formulation into and/orthrough mucosal membranes in a subject. The high-pressure delivery ofthe active agent formulation can provide for an increased diffusion rateacross the mucosal barrier, which can maximize active agent absorptioninto the cells in the mucosal layer and/or deliver the active agent tothe systemic circulation. Embodiments of the devices of the presentdisclosure include at least two reservoirs, a power reservoir and anactive agent reservoir, separated by a movable separator. In certainembodiments, the device utilizes vaporization energy to apply a force tothe movable separator, which propels the active agent formulation at ahigh velocity to facilitate penetration of the active agent into themucosal layer and thus facilitate a maximization in mucosal absorption.Accordingly, the active agent delivery devices may include any pressuregenerating element in the power reservoir for mucosal and/ortransmucosal active agent delivery, including, but not limited to,pressure-generating ingestible devices, pressure-generating sublingualdevices, pressure-generating buccal devices, pressure-generating vaginaldevices, pressure-generating nasal devices, pressure-generating oculardevices, and the like.

Aspects of the active agent delivery devices include an enclosure thathouses a power reservoir configured to produce a pressure sufficient todeliver the active agent formulation into and/or through a mucosal layerin a subject. Also provided are methods of using the device, e.g., todeliver an active agent to a human or animal subject, as well as kitsthat include the device, e.g., a sealed packaging or container havingone or more of the devices.

The penetrative process of the active agent ejection from the device maydepend on various factors, such as, but not limited to, the devicegeometry, the size and number of the nozzles for active agent release,the amount of active agent to be delivered, the viscosity and chemicalproperties of the active agent or active agent formulation to bedelivered, the mucus thickness at the site of delivery, and the intendedtarget layer of the active agent. Devices of the present disclosure canbe configured to deliver any desired active agent into and/or through amucosal layer in a subject. In certain embodiments, a pretreatment maybe used on the mucosal layer that changes the morphology and propertiesof the mucosal layer to enhance the bioavailability and increase theextent of active agent penetration into the mucosal layer. In certainembodiments, the pressure produced by the power reservoir and the activeagent penetration depth of the device can be adjusted by changing, forexample, the amount or type of pressure generating material in the powerreservoir, the dimensions of the device, the number and/or size of theactive agent delivery nozzles, which can enhance mucosal and/ortransmucosal adsorption of the active agent.

In certain embodiments, the pressure produced by the active agentdelivery device can cause mucous removal and/or decreased mucosalthickness when the ejected active agent formulation contacts the mucosallayer. In some cases, the mucosal immune system (which is immediatelybelow the mucous barrier) is exposed by the mucous removal and/ordecreased mucosal thickness. In certain instances, active agent deliveryto the mucosal immune system can be used for delivering active agents(e.g., vaccine active agents) that provoke an immune response, bothsystemic (IgG) as well as local (secretory IgA (sIgA) at the mucosa).Delivery of vaccine active agents may facilitate targeting pathogenswhose route of entry is the mucosa. In addition, because the mucosalimmune system is part of the main immune system, delivery of activeagents to the mucosal immune system may ameliorate autoimmunity, wherethe body is either over-reacting to an antigen (e.g., allergies, foodintolerance, etc.) or auto-antigen (e.g., multiple sclerosis), orunder-reacting to an auto-antigen (e.g., cancer). For example, targetingthe mucosal immune system directly may facilitate an increase in thesubject's production of an antibody response, and thus may not requiresubsequent administration of additional vaccine after the initial dose(e.g., a vaccine booster may not be required). In other instances,delivery of an active agent to the mucosal immune system may be usefulfor desensitization immunotherapy, for example where a subject isdesensitized or becomes tolerant to an allergen.

In certain instances, higher pressures may be used to deliver the activeagent systemically (e.g., through multiple layers of cells) to theblood. As described herein, the pressure produced by the power reservoirand thus the active agent penetration depth achieved by the device canbe increased by changing, for example, the amount or type of pressuregenerating material in the power reservoir, the dimensions of thedevice, the number and/or size of the active agent delivery nozzles,which can facilitate delivery of the active agent systemically.

As described herein, targeting strategies may be used to provide fordelivery of the active agent to certain target locations in a subject,e.g., intestines, stomach, nasal mucosa, buccal, endosinusial,endotracheal, enteral, intragastric, transtracheal, auricular,intraocular, retrobulbar, conjunctival, vaginal, urogenital, anal, etc.

Accordingly, aspects of the present disclosure include an active agentdelivery device that includes: an active agent reservoir at an activeagent reservoir end of the device configured to contain an active agentformulation; a power reservoir at a power reservoir end of the deviceconfigured to eject the active agent formulation at a pressuresufficient to deliver the active agent formulation into or through amucosal layer in a subject; and a moveable separator separating thepower reservoir from the active agent reservoir.

In some embodiments, the pressure generated by the device is 30 kPa ormore.

In some embodiments, the active agent formulation is ejected from thedevice in 10 msec or less.

In some embodiments, the active agent formulation is ejected from thedevice at a velocity of 1 m/s or more.

In some embodiments, the device includes a nozzle separating the activeagent reservoir from the exterior of the device.

In some embodiments, the power reservoir contains a gas generatingmaterial.

In some embodiments, the gas generating material produces a gas uponcontact with an aqueous medium.

In some embodiments, the gas is a product of a chemical reaction.

In some embodiments, the gas generating material is a volatile liquid.

In some embodiments, the volatile liquid has a vaporization temperatureranging from 37.5° C. to 45° C.

In some embodiments, the gas generating material is present in themoveable separator.

In some embodiments, the device includes a heat reservoir in heattransfer relationship with the power reservoir, where the heat reservoirincludes a heat generating material that produces heat upon contact withan aqueous medium.

In some embodiments, the device includes a valve separating the powerreservoir from the exterior of the device.

In some embodiments, the valve includes a pH responsive material.

In some embodiments, the pH responsive material includes a polymer.

In some embodiments, the device further includes an aqueous mediumreservoir configured to contact at least a portion of the powerreservoir end of the device and activate the power reservoir.

In some embodiments, the power reservoir contains a gas generatingmaterial and the aqueous medium reservoir contains an aqueous medium.

In some embodiments, the active agent includes a macromolecule.

In some embodiments, the macromolecule includes a protein.

In some embodiments, the active agent formulation includes a liquid.

In some embodiments, the device includes a tubular member having aplanar surface at the active agent reservoir end and a hemisphericalstructure at the power reservoir end.

In some embodiments, the device is configured to promote contact of theactive agent reservoir end with a mucosal surface in a subject.

Aspects of the present disclosure include a method of delivering anactive agent to a subject. The method includes administering an activeagent delivery device of the present disclosure to a subject.

In some embodiments, the method is a method of treating the subject fora disease condition.

Aspects of the present disclosure include a kit. The kit includes anactive agent delivery device of the present disclosure and a packagingcontaining the active agent delivery device.

In some embodiments, the packaging contains two or more active agentdelivery devices of the present disclosure.

In some embodiments, the kit includes a mucosal treatment agent

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides views of an active agent delivery device where thedevice is activated by a gas generating chemical reaction, according toembodiments of the present disclosure.

FIG. 2 provides views of an active agent delivery device where thedevice is activated by temperature, according to embodiments of thepresent disclosure.

FIG. 3 provides views of an active agent delivery device where the powerreservoir is included in the piston, according to embodiments of thepresent disclosure.

FIG. 4 provides views of an active agent delivery device where thedevice is activated by a gas generating chemical reaction, according toembodiments of the present disclosure.

FIG. 5A shows an image from a simulation study to evaluate the effect ofpressure on penetration depth through the intestinal wall using a deviceof the present disclosure. FIG. 5B provides a graph of the results ofsimulation studies to predict the effect of pressure in enhancing theactive agent penetration into mucosal membranes in the small intestine,according to embodiments of the present disclosure.

FIG. 6 provides a graph of the in vitro results from intestinaltransmucosal ovalbumin delivery with and without using a device of thepresent disclosure in fresh pig intestinal tissue.

FIG. 7 provides a graph of the in vitro results from buccal transmucosalovalbumin delivery with and without using a device of the presentdisclosure in fresh pig buccal tissue.

FIG. 8A provides a graph of the in vivo results from rabbit buccalvaccination against ovalbumin (OVA) with and without using a device ofthe present disclosure in New Zealand white rabbits. The graph showsblood anti-OVA IgG levels in serum over a 6 week experimental period,which shows the antibody response after buccal vaccination using adevice of the present disclosure loaded with ovalbumin. Rabbits wereimmunized two times (week 0 and after blood collection at week 4) byplacing the device inside the rabbits' cheeks and against the buccaltissue. Serum was collected on weeks 0, 1, 2, 3, 4, 5 and 6. ELISAresults are reported as optical density (OD) at 450 nm. FIG. 8B providesa graph of the in vivo results from New Zealand white rabbit buccalvaccination against ovalbumin (OVA) with and without using a device ofthe present disclosure. The graph shows the tissue anti-OVA IgA level.

FIG. 9 provides views of an active agent delivery device where thedevice is activated by a change in pH, according to embodiments of thepresent disclosure.

FIG. 10 provides views of an active agent delivery device where thedevice is activated by temperature, according to embodiments of thepresent disclosure.

FIG. 11 provides views of an active agent delivery device where thedevice is activated by a gas generating chemical reaction, according toembodiments of the present disclosure.

FIG. 12 provides views of an active agent delivery device where thedevice is activated by a gas generating chemical reaction, according toembodiments of the present disclosure.

FIG. 13A shows a photograph of an active agent delivery deviceconfigured to release an active agent formulation in 1 min or less,according to embodiments of the present disclosure.

FIG. 13B shows photographs at various time points of an active agentdelivery device configured to release an active agent formulation atabout 23 minutes, according to embodiments of the present disclosure.FIG. 13C shows photographs at various time points of an active agentdelivery device configured to release an active agent formulation atabout 2 hr and 30 min, according to embodiments of the presentdisclosure.

Before the present invention is described in greater detail, it is to beunderstood that aspects of the present disclosure are not limited to theparticular embodiments described, and as such may, of course, vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of embodiments of the present disclosurewill be defined only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within embodiments of the presentdisclosure. The upper and lower limits of these smaller ranges mayindependently be included in the smaller ranges and are also encompassedwithin embodiments of the present disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits ranges excluding either or both ofthose included limits are also included in embodiments of the presentdisclosure. In addition it is understood that the invention can be inthe form of an ingestible pill, patch and any form of a device that canbe administered or placed close to mucosal membranes as described inthis document are also included in embodiments of the present disclosure

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of embodiments of the presentdisclosure, representative illustrative methods and materials are nowdescribed. All publications and patents cited in this specification areherein incorporated by reference as if each individual publication orpatent were specifically and individually indicated to be incorporatedby reference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that embodiments of the present disclosure are not entitled toantedate such publication by virtue of prior invention. Further, thedates of publication provided may be different from the actualpublication dates which may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation. As willbe apparent to those of skill in the art upon reading this disclosure,each of the individual embodiments described and illustrated herein hasdiscrete components and features which may be readily separated from orcombined with the features of any of the other several embodimentswithout departing from the scope or spirit of the present invention. Anyrecited method can be carried out in the order of events recited or inany other order which is logically possible.

DETAILED DESCRIPTION Active Agent Delivery Devices

Provided are active agent delivery devices configured to deliver anactive agent formulation into and/or through a mucosal layer in asubject (e.g., mucosal and/or transmucosal active agent deliverydevices). The active agent delivery devices include a power reservoirconfigured to eject the active agent formulation at a pressuresufficient to deliver the active agent formulation into or through amucosal layer in a subject. For example, the active agent deliverydevices may deliver an active agent formulation into the mucosal layerin the subject, such as by delivering the active agent formulationthrough the surface of the mucosal layer into the interior of themucosal layer in the subject. In other instances, the active agentdelivery devices deliver the active agent formulation through themucosal layer in the subject, such as by delivering the active agentformulation through the thickness of the mucosal layer and to theunderlying tissues in the subject. In some cases, the active agentdelivery devices deliver the active agent formulation into and/orthrough the mucosal layer, such that the active agent is delivered tothe mucosal immune system in the subject.

Accordingly, active agent delivery devices of the present disclosure maybe configured to produce a sufficiently high pressure in the powerreservoir to propel the active agent formulation out of the device withsufficient velocity to penetrate the surface of the mucosal layer in thesubject. In some embodiments, the active agent delivery device isconfigured to produce a sufficiently high pressure, such that at least aportion of the active agent formulation penetrates the surface of themucosal layer and delivers the active agent into the mucosal layer inthe subject. In some embodiments, the active agent delivery device isconfigured to produce a sufficiently high pressure, such that at least aportion of the active agent formulation penetrates through the mucosallayer and delivers the active agent through the mucosal layer in thesubject (i.e., transmucosal delivery of the active agent). In certaininstances, the active agent delivery device is configured to produce asufficiently high pressure, such that at least a portion of the activeagent formulation penetrates through the surface of the mucosal layerand delivers the active agent to the mucosal immune system in thesubject.

As summarized above, the active agent delivery devices are designed todeliver the active agents into and/or across mucosal membranes in asubject. By “mucosal delivery” and “transmucosal delivery” is meant thatthe devices are configured, e.g., dimensioned, to be placed close toand/or in contact with a mucosal membrane of a subject and deliver anactive agent into the mucosal membrane (mucosal delivery) and/or throughthe mucosal membrane (transmucosal delivery). By mucosal membrane ismeant any mucosal layer in a subject, such as, but not limited to,buccal, endosinusial, endotracheal, enteral, intragastric,transtracheal, auricular, intraocular, retrobulbar, conjunctival,vaginal, urogenital, anal and nasal. Subjects suitable for delivery ofan active agent using a device described herein include human or animalsubjects.

To produce a sufficient pressure to deliver an active agent into and/orthrough a mucosal layer in a subject, the active agent delivery deviceincludes a power reservoir. In addition, the device includes an activeagent reservoir. The power reservoir may be positioned at a powerreservoir end of the device, and the active agent reservoir may bepositioned at an active agent reservoir end of the device. In certainembodiments, the active agent reservoir and the power reservoir arepositioned at opposing ends of the device. The power reservoir and theactive agent reservoir may be provided in an enclosure that contains thepower reservoir and active agent reservoir. In some instances, theenclosure is configured to form one or more side walls of the powerreservoir and/or active agent reservoir.

In certain embodiments, the active agent delivery device includes amovable separator (also referred to herein as a piston) that separatesthe power reservoir from the active agent reservoir. As such, themovable separator is positioned between the power reservoir and theactive agent reservoir. In some cases, the movable separator isconfigured to move inside of the enclosure, such as move in a directiontowards the active agent reservoir when a pressure is applied to themovable separator from the power reservoir. For example, the movableseparator may move into the active agent reservoir and force the activeagent formulation out of the active agent reservoir when a pressure isapplied to the movable separator from the power reservoir. The movableseparator can be shaped such that the side walls of the movableseparator are in contact with the interior walls of the device tominimize contact of the pressure generating material in the powerreservoir with the active agent formulation in the active agentreservoir. In some cases, a gap or void may be present between themovable separator and the power reservoir, which may facilitate aminimization in contact between the pressure generating material in thepower reservoir and the active agent formulation in the active agentreservoir.

Any form of pressure generating materials or devices can be used in theactive agent delivery devices of the present disclosure to produce asufficiently high pressure to deliver the active agent into and/orthrough a mucosal layer in the subject. For example, in the powerreservoir, pressure can be generated from an electro-mechanical deviceor mechanism, such as a solenoid or a piezoelectric device, or apressure generating reaction, such as a gas generating chemical reactionusing a gas generating material or a gas generating phase transitionusing a volatile liquid, combinations thereof, and the like. In certainembodiments, the active agent delivery device is self-contained. By“self-contained” is meant that the device can be activated to deliverthe active agent without providing an external pressure source or usingan external pressure generating material or device after the device isadministered to the subject. For example, as described herein, thedevice includes a power reservoir configured to produce a pressuresufficient to deliver the active agent formulation into and/or throughthe mucosal layer in the subject.

Examples of pressure generating materials that can be used in the activeagent delivery device include, but are not limited to a gas generatingmaterial, such as a gas generating material that produces a gas uponcontact with an aqueous medium (e.g., water). For example, the gasgenerating material can be a mixture of citric acid and sodiumbicarbonate. When the gas generating material contacts an aqueous medium(e.g., water or an aqueous medium contained in a subject, such as anaqueous medium in an intestine, stomach, mouth, vagina, anus, urethra,etc. of a subject), the gas generating material can produce a gas. Forinstance, when gas generating material (e.g., the mixture of citric acidand sodium bicarbonate) contacts an aqueous medium, a gas generatingchemical reaction can occur that produces a gas (e.g., carbon dioxide,CO₂). Production of a gas inside the power reservoir of the device canincrease the pressure in the power reservoir of the device. When thepressure in the power reservoir reaches a certain threshold pressure,the pressure can force the movable separator between the power reservoirand the active agent reservoir towards the active agent reservoir, thusforcing the active agent out of the active agent reservoir. Pressuregenerating materials that can be used in the active agent deliverydevices should be substantially non-toxic to the subject and should notproduce significant amounts of toxic byproducts.

In other embodiments, the pressure generating material that can be usedin the active agent delivery device is a gas generating material, suchas a gas generating material that produces a gas upon a phase transitionof the gas generating material. For example, the gas generating materialcan be a volatile liquid, such as, but not limited to, an organicsolvent (e.g., pentane, hexane, etc.). The volatile liquid may vaporizeto produce a gas. As described above, production of a gas inside thepower reservoir of the device can increase the pressure in the powerreservoir of the device. When the pressure in the power reservoirreaches a certain threshold pressure, the pressure can force the movableseparator between the power reservoir and the active agent reservoirtowards the active agent reservoir, thus forcing the active agent out ofthe active agent reservoir. In certain embodiments, the volatile liquidhas a vaporization temperature greater than the normal body temperatureof the subject. For example, if the subject is a human, the typical bodytemperature is 37° C., and in these cases the volatile liquid can have avaporization temperature greater than 37° C., such as 37.5° C. or more,or 38° C. or more, or 38.5° C. or more, or 39° C. or more, or 39.5° C.or more, or 40° C. or more, or 40.5° C. or more, or 41° C. or more, or41.5° C. or more, or 42° C. or more, or 42.5° C. or more, or 43° C. ormore, or 43.5° C. or more, or 44° C. or more, or 44.5° C. or more, or45° C. or more. In some embodiments where the subject is a human, thevolatile liquid can have a vaporization temperature ranging from 37° C.to 45° C., such as 37.5° C. to 45° C., or 37.5° C. to 43° C., or 37.5°C. to 40° C. In other instances, the volatile liquid may have avaporization temperature substantially the same as the typical bodytemperature of the subject, or slightly lower than the typical bodytemperature of the subject. For example, if the subject is a human andthe typical body temperature is 37° C., in these cases the volatileliquid can have a vaporization temperature of 37° C., or in some cases37° C. or less, or 36.5° C. or less, or 36° C. or less, or 35.5° C. orless, or 35° C. or less, such as for example a vaporization temperatureranging from 35° C. to 37° C.

In order to provide sufficient heat above the normal body temperature ofthe subject to vaporize the volatile liquid, a heat generating materialcan be included in the active agent delivery device. For example, thedevice can include an additional reservoir (e.g., a heat reservoir) thatcontains a heat generating material. The heat reservoir can bepositioned in the device in a heat transfer relationship with the powerreservoir that contains the gas generating volatile liquid. By “heattransfer relationship” is meant that the heat reservoir is positioned inthe device such that heat produced by the heat generating material inthe heat reservoir can be transferred (e.g., by thermal conduction) tothe power reservoir. The heat provided to the power reservoir from theheat generating material can be sufficient to heat the volatile liquidin the power reservoir to its vaporization temperature, such that thevolatile liquid vaporizes and produces a gas in the power reservoir,thus increasing the pressure in the power reservoir as described herein.Heat generating materials that can be used in the active agent deliverydevices include heat generating materials that produce heat upon contactwith an aqueous medium (e.g., water or an aqueous medium contained in asubject, such as an aqueous medium in an intestine, stomach, mouth,vagina, anus, urethra, etc. of a subject). Examples of heat generatingmaterials include, but are not limited to, calcium chloride, and thelike.

Pressures generated by the active agent delivery device are sufficientto deliver the active agent formulation into and/or through the mucosallayer in the subject and can be 25 kPa or more, such as 30 kPa or more,or 35 kPa or more, or 40 kPa or more, or 45 kPa or more, or 50 kPa ormore, or 55 kPa or more, or 60 kPa or more, or 65 kPa or more, or 70 kPaor more, or 75 kPa or more, or 80 kPa or more, or 85 kPa or more, or 90kPa or more, or 95 kPa or more, or 100 kPa or more, or 105 kPa or more,or 110 kPa or more, or 115 kPa or more, or 120 kPa or more, or 125 kPaor more, or 130 kPa or more, or 135 kPa or more, or 140 kPa or more, or145 kPa or more, or 150 kPa or more. In some cases, the pressuregenerated by the active agent delivery device (e.g., produced inside thepower reservoir and/or active agent reservoir) is 30 kPa. For example,the pressure generated by the active agent delivery device can rangefrom 25 kPa to 150 kPa, or 25 kPa to 125 kPa, or 25 kPa to 100 kPa, or25 kPa to 75 kPa, or 25 kPa to 50 kPa, or 30 kPa to 50 kPa. In somecases, the pressure generated by the active agent delivery device rangesfrom 30 kPa to 50 kPa. In some instances, the pressure generated by theactive agent delivery device as described above is measured as thedifference in pressure between the surrounding environment and thepressure at an active agent delivery nozzle of the device.

In certain embodiments, the active agent delivery device is configuredto release the active agent formulation contained in an active agentreservoir of the device in a short time period, such as in 10milliseconds (msec) or less, such as 9 msec or less, or 8 msec or less,or 7 msec or less, or 6 msec or less, or 5 msec or less, or 4 msec orless, or 3 msec or less, or 2 msec or less, or 1 msec or less, or 0.5msec or less, or 0.3 msec or less, or 0.1 msec or less. For example, theactive agent delivery device can release the active agent formulationcontained in an active agent reservoir of the device in a short timeperiod ranging from 0.1 msec to 10 msec, or 0.1 msec to 9 msec, or 0.1msec to 8 msec, or 0.1 msec to 7 msec, or 0.1 msec to 6 msec, or 0.1msec to 5 msec, or 0.1 msec to 4 msec, or 0.1 msec to 3 msec, or 0.1msec to 2 msec, or 0.1 msec to 1 msec, or 0.1 msec to 0.5 msec. In somecases, the active agent delivery device releases the active agentformulation contained in an active agent reservoir of the device in 5msec or less. In some cases, the active agent delivery device releasesthe active agent formulation contained in an active agent reservoir ofthe device in 4 msec or less. In some cases, the active agent deliverydevice releases the active agent formulation contained in an activeagent reservoir of the device in 3 msec or less. In some cases, theactive agent delivery device releases the active agent formulationcontained in an active agent reservoir of the device in 2 msec or less.In some cases, the active agent delivery device releases the activeagent formulation contained in an active agent reservoir of the devicein 1 msec or less.

In some embodiments, the active agent delivery device is configured torelease the active agent formulation contained in an active agentreservoir of the device at a high velocity sufficient to deliver theactive agent formulation into and/or through the mucosal layer in thesubject. For example, the velocity of the active agent formulation canbe 0.1 meter/second (m/s) or more, such as 0.5 m/s or more, or 1 m/s ormore, or 1.5 m/s or more, or 2 m/s or more, or 2.5 m/s or more, or 3 m/sor more, or 3.5 m/s or more, or 4 m/s or more, or 4.5 m/s or more, or 5m/s or more, or 5.5 m/s or more, or 6 m/s or more, or 6.5 m/s or more,or 7 m/s or more, or 7.5 m/s or more, or 8 m/s or more, or 8.5 m/s ormore, or 9 m/s or more, or 9.5 m/s or more, or 10 m/s or more. In somecases, the velocity of the active agent formulation can range from 0.1m/s to 10 m/s, such as 0.5 m/s to 9 m/s, or 1 m/s to 8 m/s, or 2 m/s to7 m/s, or 2 m/s to 6 m/s, or 2 m/s to 5 m/s, or 3 m/s to 5 m/s. Forexample, in some embodiments, the velocity of the active agentformulation released from the device is 4 m/s. In some embodiments, thevelocity of the active agent formulation released from the device is 2.5m/s.

As described above, the aqueous medium that can be used to activate thegas generating material and/or the heat generating material in theactive agent delivery device can be water or an aqueous medium in thesubject, such as an aqueous medium in an intestine, stomach, mouth,vagina, anus, urethra, etc. of the subject. In some instances, theaqueous medium used to activate the gas generating material and/or theheat generating material is provided by the surrounding environmentwithin the subject after the active agent delivery device isadministered to the subject, such as for example an aqueous medium in anintestine, stomach, mouth, vagina, anus, urethra, etc. of the subject.

In other embodiments, the aqueous medium (e.g., water) can be containedin an additional reservoir of the device (e.g., an aqueous mediumreservoir). For example, the device can include the aqueous mediumreservoir. The aqueous medium reservoir can be positioned in the deviceadjacent to the power reservoir. In some instances, a separator ispositioned between the power reservoir and the aqueous medium reservoir.The separator can be substantially impermeable to the aqueous medium,such that the aqueous medium does not prematurely contact the contentsof the power reservoir. In some cases, the separator between the powerreservoir and the aqueous medium reservoir is frangible, and the devicealso includes a puncturing element configured to puncture and/or breakthe separator between the power reservoir and the aqueous mediumreservoir. In these embodiments, when activation of the device isdesired, the puncturing element can be contacted to the separator (e.g.,by pressing the puncturing element against the separator) withsufficient force to puncture and/or break the separator, thus allowingthe aqueous medium in the aqueous medium reservoir to contact thecontents of the power reservoir. As described above, the power reservoirmay contain a gas generating material that produces a gas upon contactwith the aqueous medium.

In other embodiments, the aqueous medium reservoir can be provided as aseparate element from the active agent delivery device. The aqueousmedium reservoir can contain an aqueous medium. In some instances, theaqueous medium reservoir can include a frangible wall. In theseembodiments, the power reservoir may have an exterior surface composedof a material configured to dissolve or degrade upon contact with anaqueous medium. The aqueous medium reservoir may be configured tocontact at least a portion of the power reservoir end of the device andactivate the power reservoir. For example, the aqueous medium reservoirmay be configured to contact the exterior surface of the power reservoirwith the aqueous medium contained in the aqueous medium reservoir. Insome cases, the aqueous medium reservoir can be attached to the activeagent delivery device around the power reservoir end of the device, suchthat the frangible wall is broken and the aqueous medium is releasedfrom the aqueous medium reservoir. Contacting the exterior surface ofthe power reservoir with the aqueous medium can facilitate thedissolution and/or degradation of the dissolvable/degradable surface ofthe power reservoir, and thus allow the aqueous medium to contact thecontents of the power reservoir. As described above, the power reservoirmay contain a gas generating material that produces a gas upon contactwith the aqueous medium.

In certain embodiments, the device includes one or more nozzles on theactive agent reservoir that separate the active agent reservoir from theexterior of the device. The nozzles provide an outlet from the activeagent reservoir through which the active agent formulation can bedelivered to the mucosal layer in the subject. In some cases, a nozzleis formed by providing a hole through a wall of the active agentreservoir. For example, a nozzle hole may be provided on a surface ofthe active agent reservoir opposite from the side of the active agentreservoir that is adjacent to the movable separator in the device. Insome cases, nozzles may be provided on a side wall of the device (e.g.,on a side wall of the active agent reservoir). In certain embodiments,the nozzle may protrude from the exterior surface of the active agentreservoir. For example, the nozzle may be provided on a surface of theactive agent reservoir opposite from the side of the active agentreservoir that is adjacent to the movable separator in the device. Thenozzle can be cone shaped, cylinder shaped, pyramid shaped, frustumshaped, or may have a cross-sectional profile of a square, or arectangle, etc. In some instances, a nozzle that protrudes from asurface of the active agent reservoir may have a longitudinal axissubstantially perpendicular to the surface of the active agentreservoir. In other embodiments, the nozzle may be angled with respectto the surface of the active agent reservoir. In yet other embodiments,the nozzle can extend from a side wall of the device (e.g., extend froma side wall of the active agent reservoir). In some cases, a nozzle thatextends from a side wall of the device may facilitate delivery of theactive agent to a mucosal layer positioned alongside of the device, suchas in a nasal cavity.

In certain embodiments, the nozzle can include a valve. The valve (i.e.,the active agent reservoir valve) can be configured to release theactive agent formulation from the active agent reservoir upon a certaincondition. For instance, the active agent reservoir valve may beconfigured to release the active agent formulation from the active agentreservoir when a threshold pressure is achieved in the active agentreservoir due to the application of pressure on the active agentreservoir from the power reservoir. In other instances, the active agentreservoir valve may be configured to release the active agentformulation from the active agent reservoir in response to a change in acondition of the surrounding environment, such as, but not limited to,pH, temperature, exposure to an aqueous medium, and the like. Forexample, the active agent reservoir valve may be composed of a materialthat is a pH responsive material, such as a pH responsive material thatdissolves or degrades at a relatively low pH (e.g., pH 5 or less, or pH4 or less, or pH 3 or less, or pH 2 or less). An active agent reservoirvalve composed of a pH responsive material that dissolves or degrades atlow pH may facilitate release of the active agent in the stomach of thesubject. In other embodiments, the valve may be composed of a materialthat is a pH responsive material, such as a pH responsive material thatdissolves or degrades at a relatively higher pH (e.g., pH 5 or more, orpH 6 or more, or pH 7 or more). An active agent reservoir valve composedof a pH responsive material that dissolves or degrades at a relativelyhigher pH may facilitate release of the active agent in the intestine ofthe subject.

One or more valves may also be present on the power reservoir (i.e.,power reservoir valves). The power reservoir valve can be configured toprovide an inlet into the power reservoir upon a certain condition. Forexample, the valve on the power reservoir can provide an inlet throughwhich an aqueous medium can contact the contents of the power reservoir,e.g., to activate a pressure generating material in the power reservoir.In some instances, the power reservoir valve may be configured toprovide an inlet into the power reservoir in response to a change in acondition of the surrounding environment, such as, but not limited to,pH, temperature, exposure to an aqueous medium, and the like. Forexample, the power reservoir valve may be composed of a material that isa pH responsive material, such as a pH responsive material thatdissolves or degrades at a relatively low pH (e.g., pH 5 or less, or pH4 or less, or pH 3 or less, or pH 2 or less). A power reservoir valvecomposed of a pH responsive material that dissolves or degrades at lowpH may facilitate activation of the pressure generating material in thepower reservoir in the stomach of the subject. In other embodiments, thepower reservoir valve may be composed of a material that is a pHresponsive material, such as a pH responsive material that dissolves ordegrades at a relatively higher pH (e.g., pH 5 or more, or pH 6 or more,or pH 7 or more). A power reservoir valve composed of a pH responsivematerial that dissolves or degrades at a relatively higher pH mayfacilitate activation of the pressure generating material in the powerreservoir in the intestine of the subject.

In certain embodiments (e.g., embodiments of the active agent deliverydevice that include a heat reservoir), one or more valves may also bepresent on the heat reservoir (i.e., power reservoir valves). The heatreservoir valve can be configured to provide an inlet into the heatreservoir upon a certain condition. For example, the valve on the heatreservoir can provide an inlet through which an aqueous medium cancontact the contents of the heat reservoir, e.g., to activate a heatgenerating material in the heat reservoir. In some instances, the heatreservoir valve may be configured to provide an inlet into the heatreservoir in response to a change in a condition of the surroundingenvironment, such as, but not limited to, pH, temperature, exposure toan aqueous medium, and the like. For example, the heat reservoir valvemay be composed of a material that is a pH responsive material, such asa pH responsive material that dissolves or degrades at a relatively lowpH (e.g., pH 5 or less, or pH 4 or less, or pH 3 or less, or pH 2 orless). A heat reservoir valve composed of a pH responsive material thatdissolves or degrades at low pH may facilitate activation of the heatgenerating material in the heat reservoir in the stomach of the subject.In other embodiments, the heat reservoir valve may be composed of amaterial that is a pH responsive material, such as a pH responsivematerial that dissolves or degrades at a relatively higher pH (e.g., pH5 or more, or pH 6 or more, or pH 7 or more). A heat reservoir valvecomposed of a pH responsive material that dissolves or degrades at arelatively higher pH may facilitate activation of the heat generatingmaterial in the heat reservoir in the intestine of the subject.

The one or more valves included in the active agent delivery device(e.g., active agent reservoir valve, power reservoir valve, heatreservoir valve, etc.) can be composed of any suitable material, suchas, but not limited to a pH responsive material (e.g., a pH responsivematerial that dissolves or degrades at relatively low or relatively highpH), a temperature responsive material (e.g., a temperature responsivematerial that dissolves or degrades at or above the normal bodytemperature of the subject, such as at 37° C.), a material thatdissolves or degrades upon exposure to an aqueous medium, and the like.Examples of suitable valve materials include, but are not limited to, pHresponsive polymers, temperature responsive polymers, or polymers thatdissolve or degrade in an aqueous medium, and the like.

The active agent delivery device may have a variety of differentcross-sectional configurations, where the cross-sectional configurationis the shape defined by the walls of the enclosure containing the activeagent reservoir and the power reservoir. Cross-sectional configurationsof interest include, but are not limited to circular, rectangular,triangular, square and oval, combinations thereof, as well as irregularcross sectional configurations. In some instances, the device iscomposed of a tubular member (e.g., a cylinder) that has a planarsurface at the active agent reservoir end of the device and ahemispherical structure at the power reservoir end of the device. Inother embodiments, the active agent delivery device may be configured asa low-profile active agent delivery device. By “low-profile” is meantthat the thickness of the device is less than the length or width of thedevice. Such low-profile devices may facilitate delivery of the activeagent formulation to a mucosal layer in the subject, such as for buccaldelivery of an active agent. For example, a low-profile device may havea length or width to thickness ratio of 2:1 or more, such as 3:1 ormore, or 4:1 or more, or 5:1 or more, or 6:1 or more, or 7:1 or more, or8:1 or more, or 9:1 or more, or 10:1 or more.

Devices described herein may have varied dimensions, as desired. In someinstances, the length of the device ranges from 1 mm to 50 mm, such as 5mm to 30 mm, and including 10 mm to 20 mm. The outer diameter of thedevice may vary, ranging in some instances from 1 mm to 30 mm, such as 5mm to 20 mm and including 5 mm to 10 mm. The inner diameter of thedevice may also vary, ranging from 0.5 mm to 29.99 mm, such as 3.0 mm to19.99 mm and including 3.0 mm to 9.99 mm. The walls of the device mayvary in thickness, so long as the walls are sufficiently thick to holdthe active agent formulation in the active agent reservoir, sufficientlythick to hold the pressure generating material in the power reservoirand/or sufficiently thick to hold the heat generating material in theheat reservoir, and so long as the walls are sufficiently thick toprovide for the desired pressure within the power reservoir and/or theactive agent reservoir without unintended rupture of the device. In someinstances, the walls range in thickness from 0.01 mm to 2 mm, such as0.01 mm to 0.2 mm and including 0.01 mm to 0.1 mm. The dimensions may beconstant or variable in the device, as desired. For example, the innerdiameter may be constant along the length of the device, or may vary.

Device components may be fabricated from any convenient material usingany convenient protocol. Materials of interest from which the devicecomponents may be fabricated include physiologically acceptablepolymeric materials that are used in conventional pharmaceutical dosageforms and/or medical devices or implants. The materials may be clear oropaque, and may be colored as desired. Of interest are both rigid andelastic materials. For example, a device having rigid walls mayfacilitate generating a sufficient pressure to deliver an active agentformulation into and/or through mucosal membranes in a subject. Thedevices may be fabricated using and convenient fabrication protocol,including but not limited to, 3D printing, molding, and the like.

Suitable polymers from which device components (e.g., the enclosure ofthe device, the power reservoir, the active agent reservoir, the heatreservoir, the nozzle, the valves, etc.) may be fabricated include, butare not limited to: gelatins, polyvinyl alcohol (PVA); natural andsynthetic polysaccharides, including pullulan, carrageenan, xanthan,chitosan agar gums, and cellulosic materials, such ascarboxymethylcellulose, hydroxypropylmethylcellulose (HPMC),methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose,hydroxypropylcellulose; polyethylene glycols (PEGs), polyethylene oxides(PEOs), mixtures of PEGs and PEOs; acrylic and methacrylic acid basedpolymers, such as EUDRAGIT E™, EUDRAGIT L™ and/or EUDRAGIT S™methacrylic acid polymers), EUDRAGIT RL™ and/or EUDRAGIT RS™ ammoniummethacrylate copolymers; povidone (polyvinyl pyrrolidone),polyglycolysed glycerides (such as GELUCIRE 44/14™, GELUCIRE 50/02™,GELUCIRE50/13™ and GELUCIRE53/10™ polymers); carboxyvinyl polymers (suchas CARBOPOL™ polymers); polyoxyethylene-polyoxypropylene copolymers(such as POLOXAMER188™ polymer); and the like.

The device components may be fabricated using any convenient protocol,including molding, 3D printing, etc. Fabrication protocols of interestinclude, but are not limited to, those described in U.S. Pat. Nos.5,705,189; 4,576,284; 4,591,475; 4,655,840; 4,738,724; 4,738,817 and4,790,881; the disclosures of which are herein incorporated byreference.

A variety of active agents may be delivered by the active agent deliverydevices described herein. In embodiments of the device, the active agentformulation includes an active agent component (made of a single type ofactive agent or two or more different types of active agents). The term“active agent” refers to any compound or mixture of compounds whichproduces a desired physiological result in the subject, e.g., abeneficial or useful result, such as a therapeutic result, upon contactwith a living organism, e.g., an animal, such as a human. Active agentsare distinguishable from other components of the active agentformulation, such as carriers, diluents, lubricants, binders, colorants,etc. The active agent may be any molecule, as well as a binding portionor fragment thereof, that is capable of modulating a biological processin a living subject. In certain embodiments, the active agent may be asubstance used in the diagnosis, treatment, or prevention of a diseaseor as a component of a medication.

The active agent is a compound that interacts with a target in a livingsubject. The target may be a number of different types of naturallyoccurring structures, where targets of interest include bothintracellular and extra-cellular targets. Such targets may be proteins,phospholipids, nucleic acids, and the like. The active agent may includeone or more functional groups that provide for structural interactionwith the target, e.g., groups that provide for hydrophobic, hydrophilic,electrostatic or covalent interactions, depending on the particularactive agent and its intended target, where functional groups ofinterest include groups that participate in hydrogen bonding,hydrophobic-hydrophobic interactions, electrostatic interactions, etc.,and may include at least an amine, amide, sulfhydryl, carbonyl, hydroxylor carboxyl group, such as at least two functional chemical groups.Active agents of interest may include cyclical carbon or heterocyclicstructures and/or aromatic or polyaromatic structures substituted withone or more of the above functional groups. Also of interest as moietiesof active agents are structures found among biomolecules, includingproteins, peptides, vaccines, adjuvants, saccharides, fatty acids,steroids, purines, pyrimidines, derivatives, structural analogs, orcombinations thereof. Such compounds may be screened to identify thoseof interest using any convenient screening protocol.

The active agents may be derived from a naturally-occurring or syntheticcompound that may be obtained from a wide variety of sources, includingfood, pollens and libraries of synthetic or natural compounds. Forexample, numerous protocols are available for random and directedsynthesis of a wide variety of organic compounds and biomolecules,including the preparation of randomized oligonucleotides andoligopeptides. Alternatively, libraries of natural compounds in the formof bacterial, fungal, plant and animal extracts are available or readilyproduced. Additionally, natural or synthetically produced libraries andcompounds are readily modified through conventional chemical, physicaland biochemical means, and may be used to produce combinatoriallibraries. Known pharmacological agents may be subjected to directed orrandom chemical modifications, such as acylation, alkylation,esterification, amidification, etc. to produce structural analogs.

As such, the active agent may be obtained from a library ofnaturally-occurring or synthetic molecules, including a library ofcompounds produced through combinatorial means, i.e., a compounddiversity combinatorial library. When obtained from such libraries, theactive agent employed will have demonstrated some desirable activity inan appropriate screening assay for the activity. Combinatoriallibraries, as well as methods for producing and screening suchlibraries, are known in the art and described in: U.S. Pat. Nos.5,741,713; 5,734,018; 5,731,423; 5,721,099; 5,708,153; 5,698,673;5,688,997; 5,688,696; 5,684,711; 5,641,862; 5,639,603; 5,593,853;5,574,656; 5,571,698; 5,565,324; 5,549,974; 5,545,568; 5,541,061;5,525,735; 5,463,564; 5,440,016; 5,438,119; 5,223,409, the disclosuresof which are herein incorporated by reference.

Active agents of interest include both small molecule and large moleculeactive agents, including macromolecule active agents. Small moleculeactive agents include those that are 5,000 daltons (Da) or less, such as2,500 daltons or less, or 1,000 daltons or less. Large molecule activeagents include those that are 5,000 daltons or more, or 7,500 daltons ormore, such as 10,000 daltons or more, including 50,000 daltons or more,such as 100,000 daltons or more. In some instances, the active agent isa macromolecule, e.g., a very large molecule, such as a colloidalparticle, protein, or a polymer, that may be composed of hundreds orthousands of atoms.

Broad categories of active agents of interest include, but are notlimited to: cardiovascular agents; pain-relief agents, e.g., analgesics,anesthetics, anti-inflammatory agents, etc.; nerve-acting agents;chemotherapeutic (e.g., anti-neoplastic) agents; vaccines; therapeuticproteins; antigens, epitopes and hormones etc. Active agents of interestinclude, but are not limited to: antibiotics, such as: aminoglycosides,e.g. amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin,dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin,micronomcin, neomycin, netilmicin, paromycin, ribostamycin, sisomicin,spectinomycin, streptomycin, tobramycin, trospectomycin; amphenicols,e.g. azidamfenicol, chloramphenicol, florfenicol, and theimaphenicol;ansamycins, e.g. rifamide, rifampin, rifamycin, rifapentine, rifaximin;b-lactams, e.g. carbacephems, carbapenems, cephalosporins, cehpamycins,monobactams, oxaphems, penicillins; lincosamides, e.g. clinamycin,lincomycin; macrolides, e.g. clarithromycin, dirthromycin, erythromycin,etc.; polypeptides, e.g. amphomycin, bacitracin, capreomycin, etc.;tetracyclines, e.g. apicycline, chlortetracycline, clomocycline,minocycline, etc.; synthetic antibacterial agents, such as2,4-diaminopyrimidines, nitrofurans, quinolones and analogs thereof,sulfonamides, sulfones; antifungal agents, such as: polyenes, e.g.amphotericin B, candicidin, dermostatin, filipin, fungichromin,hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin,pecilocin, perimycin; synthetic antifungals, such as allylamines, e.g.butenafine, naftifine, terbinafine; imidazoles, e.g. bifonazole,butoconazole, chlordantoin, chlormidazole, etc., thiocarbamates, e.g.tolciclate, triazoles, e.g. fluconazole, itraconazole, terconazole;anthelmintics, such as: arecoline, aspidin, aspidinol, dichlorophene,embelin, kosin, napthalene, niclosamide, pelletierine, quinacrine,alantolactone, amocarzine, amoscanate, ascaridole, bephenium,bitoscanate, carbon tetrachloride, carvacrol, cyclobendazole,diethylcarbamazine, etc.; antimalarials, such as: acedapsone,amodiaquin, arteether, artemether, artemisinin, artesunate, atovaquone,bebeerine, berberine, chirata, chlorguanide, chloroquine,chlorprogaunil, cinchona, cinchonidine, cinchonine, cycloguanil,gentiopicrin, halofantrine, hydroxychloroquine, mefloquinehydrochloride, 3-methylarsacetin, pamaquine, plasmocid, primaquine,pyrimethamine, quinacrine, quinidine, quinine, quinocide, quinoline,dibasic sodium arsenate; antiprotozoan agents, such as: acranil,tinidazole, ipronidazole, ethylstibamine, pentamidine, acetarsone,aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, suramin;cardioprotective agents, e.g., Zinecard (dexrazoxane); blood modifiers,including anticoagulants (e.g., coumadin (warfarin sodium), fragmin(dalteparin sodium), heparin, innohep (tinzaparin sodium), lovenox(enoxaparin sodium), orgaran (danaparoid sodium)) antiplatelet agents(e.g., aggrasta (tirofiban hydrochloride), aggrenox (aspirin/extendedrelease dipyridamole), agrylin (anagrelide hydrochloride), ecotrin(acetylsalicylic acid), folan (epoprostenol sodium), halfprin (entericcoated aspirin), integrlilin (eptifibatide), persantine (dipyridamoleUSP), plavix (clopidogrel bisulfate), pletal (cilostazol), reopro(abciximab), ticlid (ticlopidine hydrochloride)), thrombolytic agents(activase (alteplase), retavase (reteplase), streptase (streptokinase));adrenergic blockers, such as cardura (doxazosin mesylate), dibenzyline(phenoxybenzamine hydrochloride), hytrin (terazosin hydrochloride),minipress (prazosin hydrochloride), minizide (prazosinhydrochloride/polythiazide); adrenergic stimulants, such as aldoclor(methyldopa—chlorothiazide), aldomet (methyldopa, methyldopate HCl),aldoril (methyldopa—hydrochlorothiazide), catapres (clonidinehydrochloride USP, clonidine), clorpres (clonidine hydrochloride andchlorthalidone), combipres (clonidine hydrochloride/chlorthalidone),tenex (guanfacine hydrochloride); alpha/bet adrenergic blockers, such ascoreg (carvedilol), normodyne (labetalol hydrochloride); angiotensinconverting enzyme (ACE) inhibitors, such as accupril (quinaprilhydrochloride), aceon (perindopril erbumine), altace (ramipril),captopril, lotensin (benazepril hydrochloride), mavik (trandolapril),monopril (fosinopril sodium tablets), prinivil (lisinopril), univasc(moexipril hydrochloride), vasotec (enalaprilat, enalapril maleate),zestril (lisinopril); angiotensin converting enzyme (ACE) inhibitorswith calcium channel blockers, such as lexxel (enalaprilmaleate—felodipine ER), lotrel (amlodipine and benazeprilhydrochloride), tarka (trandolapril/verapamil hydrochloride ER);angiotensin converting enzyme (ACE) inhibitors with diuretics, such asaccuretic (quinapril HCl/hydroclorothiazide), lotensin (benazeprilhydrochloride and hydrochlorothiazide USP), prinizide(lisinopril—hydrochlorothiazide), uniretic (moexiprilhydrochloride/hydro chlorothiazide), vaseretic (enalaprilmaleate—hydrochlorothiazide), zestoretic (lisinopril andhydrochlorothiazide); angiotensin II receptor antagonists, such asatacand (candesartan cilexetil), avapro (irbesartan), cozaar (losartanpotassium), diovan (valsartan), micardis (telmisartan), teveten(eprosartan mesylate); angiotensin II receptor antagonists withdiuretics, such as avalide (irbesartan—hydrochlorothiazide), diovan(valsartan and hydrochlorothiazide), hyzaar (losartanpotassium—hydrochlorothiazide); antiarrhythmics, such as Group I (e.g.,mexitil (mexiletine hydrochloride, USP), norpace (disopyramidephosphate), procanbid (procainamide hydrochloride), quinaglute(quinidine gluconate), quinidex (quinidine sulfate), quinidine(quinidine gluconate injection, USP), rythmol (propafenonehydrochloride), tambocor (flecainide acetate), tonocard (tocainideHCl)), Group II (e.g., betapace (sotalol HCl), brevibloc (esmololhydrochloride), inderal (propranolol hydrochloride), sectral (acebutololhydrochloride)), Group III (e.g., betapace (sotalol HCl), cordarone(amiodarone hydrochloride), corvert (ibutilide fumarate injection),pacerone (amiodarone HCl), tikosyn (dofetilide)), Group IV (e.g., calan(verapamil hydrochloride), cardizem (diltiazem HCl), as well asadenocard (adenosine), lanoxicaps (digoxin), lanoxin (digoxin));antilipemic acids, including bile acid sequestrants (e.g., colestid(micronized colestipol hydrochloride), welchol (colesevelamhydrochloride)), fibric acid derivatives (e.g., atromid (clofibrate),lopid (gemfibrozal tablets, USP), tricor (fenofibrate capsules)),HMG-CoA reductase inhibitors (e.g., baycol (cerivastatin sodiumtablets), lescol (fluvastatin sodium), lipitor (atorvastatin calcium),mevacor (lovastatin), pravachol (pravastatin sodium), zocor(simvastatin)), Nicotinic Acid (e.g., Niaspan (niacin extended releasetablets)); beta adrenergic blocking agents, e.g., betapace (sotalolHCl), blocadren (timolol maleate), brevibloc (esmolol hydrochloride),cartrol (carteolol hydrochloride), inderal (propranolol hydrochloride),kerlone (betaxolol hydrochloride), nadolol, sectral (acebutololhydrochloride), tenormin (atenolol), toprol (metoprolol succinate),zebeta (bisoprolol fumarate); beta adrenergic blocking agents withdiuretics, e.g., corzide (nadolol and bendroflumethiazide tablets),inderide (propranolol hydrochloride and hydroclorothiazide), tenoretic(atenolol and chlorthalidone), timolide (timololmaleate—hydrochlorothiazide), ziac (bisoprolol fumarate andhydrochlorothiazide); calcium channel blockers, e.g., adalat(nifedipine), calan (verapamil hydrochloride), cardene (nicardipinehydrochloride), cardizem (diltiazem HCl), covera (verapamilhydrochloride), isoptin (verapamil hydrochloride), nimotop (nimodipine),norvasc (amlodipine besylate), plendil (felodipine), procardia(nifedipine), sular (nisoldipine), tiazac (diltiazem hydrochloride),vascor (bepridil hydrochloride), verelan (verapamil hydrochloride);diuretics, including carbonic anhydrase inhibitors (e.g., daranide(dichlorphenamide)), combination diuretics (e.g., aldactazide(spironolactone with hydrochlorothiazide), dyazide (triamterene andhydrochlorothiazide), maxzide (triamterene and hydrochlorothiazide),moduretic (amiloride HCl—hydrochlorothiazide)), loop diuretics (demadex(torsemide), edecrin (ethacrynic acid, ethacrynate sodium), furosemide),potassium-sparing diuretics (aldactone (spironolactone), dyrenium(triamterene), midamor (amiloride HCl)), thiazides & related diuretics(e.g., diucardin (hydroflumethiazide), diuril (chlorothiazide,chlorothiazide sodium), enduron (methyclothiazide), hydrodiurilhydrochlorothiazide), indapamide, microzide (hydrochlorothiazide) mykrox(metolazone tablets), renese (polythi-azide), thalitone (chlorthalidone,USP), zaroxolyn (metolazone)); inotropic agents, e.g., digitek(digoxin), dobutrex (dobutamine), lanoxicaps (digoxin), lanoxin(digoxin), primacor (milrinone lactate); activase (alteplaserecombinant); adrenaline chloride (epinephrine injection, USP); demser(metyrosine), inversine (mecamylamine HCl), reopro (abciximab), retavase(reteplase), streptase (streptokinase), tnkase (tenecteplase);vasodilators, including coronary vasodilators (e.g., imdur (isosorbidemononitrate), ismo (isosorbide mononitrate), isordil (isosorbidedinitrate), nitrodur (nitroglycerin), nitrolingual (nitroglycerinlingual spray), nitrostat (nitroglycerin tablets, USP), sorbitrate(isosorbide dinitrate)), peripheral vasodilators & combinations (e.g.,corlopam (fenoldopam mesylate), fiolan (epoprostenol sodium), primacor(milrinone lactate)), vasopressors, e.g., aramine (metaraminolbitartrate), epipen (EpiPen 0.3 mg brand of epinephrine auto injector,EpiPen Jr. 0.15 mg brand of epinephrine auto injector), proamatine(midodrine hydrochloride); etc.; psychopharmacological agents, such as(1) central nervous system depressants, e.g. general anesthetics(barbiturates, benzodiazepines, steroids, cyclohexanone derivatives, andmiscellaneous agents), sedative-hypnotics (benzodiazepines,barbiturates, piperidinediones and triones, quinazoline derivatives,carbamates, aldehydes and derivatives, amides, acyclic ureides,benzazepines and related drugs, phenothiazines, etc.), central voluntarymuscle tone modifying drugs (anticonvulsants, such as hydantoins,barbiturates, oxazolidinediones, succinimides, acylureides,glutarimides, benzodiazepines, secondary and tertiary alcohols,dibenzazepine derivatives, valproic acid and derivatives, GABA analogs,etc.), analgesics (morphine and derivatives, oripavine derivatives,morphinan derivatives, phenylpiperidines, 2,6-methane-3-benzazocainederivatives, diphenylpropylamines and isosteres, salicylates,p-aminophenol derivatives, 5-pyrazolone derivatives, arylacetic acidderivatives, fenamates and isosteres, etc.) and antiemetics(anticholinergics, antihistamines, antidopaminergics, etc.), (2) centralnervous system stimulants, e.g. analeptics (respiratory stimulants,convulsant stimulants, psychomotor stimulants), narcotic antagonists(morphine derivatives, oripavine derivatives, 2,6-methane-3-benzoxacinederivatives, morphinan derivatives) nootropics, (3)psychopharmacologicals, e.g., anxiolytic sedatives (benzodiazepines,propanediol carbamates) antipsychotics (phenothiazine derivatives,thioxanthine derivatives, other tricyclic compounds, butyrophenonederivatives and isosteres, diphenylbutylamine derivatives, substitutedbenzamides, arylpiperazine derivatives, indole derivatives, etc.),antidepressants (tricyclic compounds, MAO inhibitors, etc.), (4)respiratory tract drugs, e.g. central antitussives (opium alkaloids andtheir derivatives); pharmacodynamic agents, such as (1) peripheralnervous system drugs, e.g. local anesthetics (ester derivatives, amidederivatives), (2) drugs acting at synaptic or neuroeffector junctionalsites, e.g. cholinergic agents, cholinergic blocking agents,neuromuscular blocking agents, adrenergic agents, antiadrenergic agents,(3) smooth muscle active drugs, e.g. spasmolytics (anticholinergics,musculotropic spasmolytics), vasodilators, smooth muscle stimulants, (4)histamines and antihistamines, e.g. histamine and derivative thereof(betazole), antihistamines (H1-antagonists, H2-antagonists), histaminemetabolism drugs, (5) cardiovascular drugs, e.g. cardiotonics (plantextracts, butenolides, pentadienolids, alkaloids from erythrophleumspecies, ionophores, -adrenoceptor stimulants, etc), antiarrhythmicdrugs, antihypertensive agents, antilipidemic agents (clofibric acidderivatives, nicotinic acid derivatives, hemostyptics, (6) blood andhemopoietic system drugs, e.g., antianemia drugs, blood coagulationdrugs (hemostatics, anticoagulants, antithrombotics, thrombolytics,blood proteins and their fractions), (7) gastrointestinal tract drugs,e.g. digestants (stomachics, choleretics), antiulcer drugs,antidiarrheal agents, (8) locally acting drugs; chemotherapeutic agents,such as (1) anti-infective agents, e.g. ectoparasiticides (chlorinatedhydrocarbons, pyrethins, sulfurated compounds), anthelmintics,antiprotozoal agents, antimalarial agents, antiamebic agents,antileiscmanial drugs, antitrichomonal agents, antitrypanosomal agents,sulfonamides, antimycobacterial drugs, antiviral chemotherapeutics,etc., and (2) cytostatics, i.e. antineoplastic agents or cytotoxicdrugs, such as alkylating agents, e.g. Mechlorethamine hydrochloride(Nitrogen Mustard, Mustargen, HN2), Cyclophosphamide (Cytovan,Endoxana), Ifosfamide (IFEX), Chlorambucil (Leukeran), Melphalan(Phenylalanine Mustard, L-sarcolysin, Alkeran, L-PAM), Busulfan(Myleran), Thiotepa (Triethylenethiophosphoramide), Carmustine (BiCNU,BCNU), Lomustine (CeeNU, CCNU), Streptozocin (Zanosar) and the like;plant alkaloids, e.g., Vincristine (Oncovin), Vinblastine (Velban,Velbe), Paclitaxel (Taxol), and the like; antimetabolites, e.g.Methotrexate (MTX), Mercaptopurine (Purinethol, 6-MP), Thioguanine(6-TG), Fluorouracil (5-FU), Cytarabine (Cytosar-U, Ara-C), Azacitidine(Mylosar, 5-AZA) and he like; antibiotics, e.g. Dactinomycin(Actinomycin D, Cosmegen), Doxorubicin (Adriamycin), Daunorubicin(duanomycin, Cerubidine), Idarubicin (Idamycin), Bleomycin (Blenoxane),Picamycin (Mithramycin, Mithracin), Mitomycin (Mutamycin) and the like,and other anticellular proliferative agents, e.g. Hydroxyurea (Hydrea),Procarbazine (Mutalane), Dacarbazine (DTIC-Dome), Cisplatin (Platinol)Carboplatin (Paraplatin), Asparaginase (Elspar) Etoposide (VePesid,VP-16-213), Amsarcrine (AMSA, m-AMSA), Mitotane (Lysodren), Mitoxantrone(Novatrone), and the like.

Drug compounds of interest are also listed in: Goodman & Gilman's, ThePharmacological Basis of Therapeutics (9th Ed) (Goodman et al. eds)(McGraw-Hill) (1996); and 2001 Physician's Desk Reference.

Specific categories and examples of active agents include, but are notlimited to those appearing the following table:

Therapeutic Category Pharmacological Class Structural ExamplesAnalgesics Opioid Analgesics Includes drugs such as Morphine, Meperidineand Propoxyphene Non-opioid Analgesics Includes drugs such as SodiumSalicylate, Diflunisal, Para-Aminophenol Derivatives, Anthranilic AcidDerivatives, and Phenylpropionic Acid Derivatives AnestheticsAntibacterials Beta-lactam, Cephalosporins Beta-lactam, PenicillinsBeta-lactam, Other Includes drugs such as Loracarbef MacrolidesQuinolones Sulfonamides Tetracyclines Antibacterials, Other Includesdrugs such as Trimethoprim, Vancomycin, Lincomycin, Clindamycin,Furazolidone, Nitrofurantoin, Linezolid, Bacitracin, Chloramphenicol,Daptomycin, Fosfomycin, Methenamine, Metronidazole, Mupirocin,Rifaximin, Spectinomycin Anticonvulsants Calcium Channel ModifyingIncludes drugs such as Nifedipine Agents Gamma-aminobutyric AcidIncludes drugs such as Clonazepam, Diazepam, and (GABA) AugmentingAgents Phenobarbital Glutamate Reducing Agents Sodium Channel InhibitorsAntidementia Agents Cholinesterase Inhibitors Glutamate PathwayModifiers Antidementia Agents, Other Includes drugs such as ErgoloidMesylates Antidepressants Monoamino Oxidase (Type A) Inhibitors ReuptakeInhibitors Antidepressants, Other Includes drugs such as Bupropion,Maprotiline, Mirtazapine, Trazodone Antiemetics Antifungals Includesdrugs such as Amphotericin B, and Ketoconazole Antigout AgentsAnti-inflammatories Glucocorticoids See Adrenal Pharmacologic Class forsimilar/related therapies Nonsteroidal Anti- See Non-opioid AnalgesicsPharmacologic Class for inflammatory Drugs (NSAIDs) similar/relatedtherapies Antimigraine Agents Abortive See Analgesics TherapeuticCategory for similar/related therapies Prophylactic See Autonomic Agentsand Cardiovascular Agents Therapeutic Categories for similar/relatedtherapies Antimycobacterials Antituberculars Includes drugs such asIsoniazid, Pyridoxine and Cycloserine Antimycobacterials, Other Includesdrugs such as Clofazimine, Dapsone, Rifabutin Antineoplastics AlkylatingAgents Includes drugs such as Chlorambucil, Thiotepa, Busulfan,Dacarbazine, and Carmustine Antimetabolites Includes drugs such asMethotrexate, Cytarabine, and Mercaptopurine Immune Modulators andIncludes biotech drugs as various Monoclonal Antibodies, VaccinesCytokines, Interferones and Interleukins Molecular Target InhibitorsIncludes drugs such as Vaccines, Antisense and Gene Tharapies NucleosideAnalogues Includes drugs such as dIdC, and AZT Protective AgentsIncludes biotech drugs as Vaccines Topoisomerase InhibitorsAntineoplastics, Other Includes drugs such as Carboplatin, Cisplatin,Oxaliplatin Antiparasitics Anthelmintics Includes drugs such asMebendazole, Pyrantel Pamoate, Bithionol, and Paromomycin AntiprotozoalsIncludes drugs such as Chloroquine, Pyrimethamine, Metronidazole,Furazolidone, Melarsoprol, Suramin and TetracyclinesPediculicides/Scabicides Includes drugs such as Crotamiton, Lindane,Benzyl Benzoate and Sulfur Antiparkinson Agents CatecholO-methyltransferase (COMT) Inhibitors Dopamine Agonists Includes drugssuch as Levodopa, and Deprenyl Antiparkinson Agents, Other Includesdrugs such as Benztropine, Biperidin, Bromocriptine, Diphenhydramine,Procyclidine, Selegiline, Trihexyphenidyl AntipsychoticsNon-phenothiazines Includes drugs such as Chlorprothixene, andThiothixene Non-phenothiazines/Atypicals Includes drugs such asHaloperidol, Molindone, and Loxapine Phenothiazines Includes drugs suchas Fluphenazine Antivirals Anti-cytomegalovirus (CMV) Includes biotechdrugs as Vaccines Agents Antiherpetic Agents Includes biotech drugs asVaccines and Recombinant Proteins Anti-human immunodeficiency virus(HIV) Agents, Fusion Inhibitors Anti-HIV Agents, Non-nucleoside ReverseTranscriptase Inhibitors Anti-HIV Agents, Nucleoside and NucleotideReverse Transcriptase Inhibitors Anti-HIV Agents, Protease InhibitorsAnti-influenza Agents Includes biotech drugs such as Vaccines, Flumist,and Thymidine Kinase Inhibitors Antivirals, Other Includes drugs such asAdefovir and Ribavirin Anxiolytics Antidepressants Anxiolytics, OtherIncludes drugs such as Buspirone and Meprobamate Autonomic AgentsParasympatholytics Parasympathomimetics Sympatholytics SeeCardiovascular Agents and Genitourinary Agents Therapeutic Categoriesfor similar/related therapies Sympathomimetics See Cardiovascular AgentsTherapeutic Category for similar/related therapies Bipolar Agents BloodGlucose Antihypoglycemics Regulators Hypoglycemics, Oral Insulins BloodAnticoagulants Includes drugs such as Acetaminophen, CoumarinProducts/Modifiers/ Derivatives, Aspirin, Heparin, and IndandioneDerivatives Volume Expanders Blood Formation Products CoagulantsPlatelet Aggregation Inhibitors Cardiovascular Agents Alpha-adrenergicAgonists See Autonomic Agents Therapeutic Category for similar/relatedtherapies Alpha-adrenergic Blocking Includes drugs such as PhenolamineMesylate, and Agents Prazosin HCl Antiarrhythmics Includes drugs such asBretylium, Digitalis, Quinidine, and Atropine Beta-adrenergic BlockingIncludes drugs such as Atenolol and related compounds Agents CalciumChannel Blocking Includes drugs such as Nifedipine Agents Direct CardiacInotropics Diuretics Includes drugs such as Furosemide, andSpironolactone Dyslipidemics Renin-angiotensin-aldosterone Includesdrugs such as Captopril, and Saralasin Acetate System InhibitorsVasodilators Includes drugs such as Sodium Nitroprusside, NitroglycerineCentral Nervous Amphetamines System Agents Non-amphetamines Dental andOral Includes such drugs as CHG Agents Dermatological DermatologicalAnesthetics Includes drugs such as Lidocaine, Dibucaine, and AgentsDiperodon Dermatological Antibacterials Includes drugs such asBacitracin, Chlorotetracycline, and Erythromycin DermatologicalAntifungals Includes drugs such as Haloprogin, Tolnaftate, Imidazoles,and Polyene Antibiotics Dermatological Anti- Includes drugs such asHydrocortisone, Amcinonide, and inflammatories Desonide DermatologicalAntipruritic Includes drugs such as Benzocaine, Lidocaine, Pramoxine,Agents Diphenhydramine, and Hydrocortisone Dermatological AntiviralsHIV-Inhibitors of reverse transcriptase (Nucleoside analogs,Non-nucleoside analogs, and Nucleotide analogs), Viral packaginginhibitors (Protease Inhibitors), Fusion Inhibitors, HerpesVirus-Nucleoside analogs (Acyclovir, Valacyclovir, Famciclovir andPenciclovir), Interferone Alpha, and Imiquimod DermatologicalKeratolytics Includes drugs such as Urea, and Salicylic AcidDermatological Mitotic Includes drugs such as Vinblastine, andVincristine Inhibitors Dermatological Includes drugs such asHydroquinone and Trioxsalen Photochemotherapy Agents DermatologicalRetinoids Includes drugs such as Tretinoin Dermatological Tar Includesdrugs such as Anthraquinone derivatives Derivatives (Anthralin)Dermatological Vitamin D Includes drugs such as Calcitriol, andCalcipotriol Analogs Dermatological Wound Care Includes drugs such asCollagenase, Sutilains and Agents Dextranomers Dermatological AntiacneIncludes drugs such as Benzoyl Peroxide, and Salicylic AcidDermatological UVA/UVB Includes actives such as 3_Benzylidene_Camphors,2- Block phenylbenzimidazole-5-sulfonic acid, Octyl Salicylate,Homosalate, Octylmethyl PABA,, Octyl Methoxycinnamate, Octocrylene,Oxybenzone, Menthyl Anthranilate, Titanium Dioxide, Zinc Oxide,Avobenzone Deterrents/Replacements Alcohol Deterrents EnzymeReplacements/Modifiers Gastrointestinal Antispasmodics, AgentsGastrointestinal Histamine2 (H2) Blocking Includes drugs such asCimetidine, and Ranitidine Agents Irritable Bowel Syndrome AgentsProtectants Proton Pump Inhibitors Gastrointestinal Agents, OtherIncludes drugs such as Sevelamer, Ursodiol, Antisense, Vaccines and Maband their fragments Genitourinary Agents Antispasmodics, Urinary BenignProstatic Hypertrophy See Autonomic Agents and Cardiovascular AgentsAgents Therapeutic Categories for similar/related therapies ImpotenceAgents Prostaglandins See Hormonal Agents,Stimulant/Replacement/Modifying TherapeuticCategory for similar/relatedtherapies Hormonal Agents, Adrenal See Anti-inflammatories TherapeuticCategory for Stimulant/Replacement/ similar/related therapies ModifyingParathyroid/Metabolic Bone Disease Agents Pituitary Prostaglandins SeeGenitourinary Agents Therapeutic Category for similar/related therapiesSex Hormones/Modifiers Thyroid Includes drugs such as LevothyroxineSodium, and Methimazole Hormonal Agents, Adrenal Suppressant PituitaryIncludes biotech drugs as hGH Sex Hormones/Modifiers Includes biotechdrugs as Estradiol Thyroid Immunological Agents Immune StimulantsIncludes biotech drugs as various Monoclonal Antibodies, Interferonesand Interleukins Immune Suppressants Includes biotech drugs as variousMonoclonal Antibodies, Interferones and Interleukins ImmunomodulatorsIncludes biotech drugs as various Monoclonal Antibodies, Interferonesand Interleukins Inflammatory Bowel Glucocorticoids See Hormonal Agents,Stimulant/Replacement/Modifying Disease Agents Therapeutic Category forsimilar/related therapies Salicylates Sulfonamides See AntibacterialsTherapeutic Category for similar/related therapies Ophthalmic AgentsOphthalmic Anti-allergy Includes drugs such as Cromolyn AgentsOphthalmic Antibacterials Includes drugs such as Bacitracin,Chloramphenicol, Erythromycin, and Polymyxin B Sulfate OphthalmicAntifungals Includes drugs such as Amphotericin B, Miconazole, Natamycinand Nystatin Ophthalmic Antiglaucoma Includes drugs such as PilocarpineHCl, Carbachol, Agents Physostigmine Salicylate, Isoflurophate, andAcetazolamide Ophthalmic Anti- Includes drugs such as Hydrocortisone,Dexamethasone, inflammatories and Medrysone Ophthalmic AntiviralsIncludes drugs such as Idoxuridine, Trifluridine, Antisense, andVidarabine Ophthalmics, Other Includes drugs such as Formivirsen OticAgents Otic Antibacterials Includes drugs such as Chloramphenicol,Neomycin Sulfate, and Polymyxins Otic Anti-inflammatories RespiratoryTract Antihistamines Agents Antileukotrienes Bronchodilators,Anticholinergic Bronchodilators, Anti- Includes drugs such asCorticosteroid derivatives inflammatories Bronchodilators,Phosphodiesterase 2 Inhibitors (Xanthines) Bronchodilators, Includesdrugs such as Albuterol, Terbutaline, and Sympathomimetic IsoproterenolMast Cell Stabilizers Includes drugs such as Cromolyn Sodium MucolyticsRespiratory Tract Agents, Includes drugs such as Alpha-1-proteinaseInhibitor, Other Human; Benzonatate; Guaifenesin; Iodinated Glycerol;Potassium Iodide; Tetrahydrozoline Sedatives/Hypnotics Skeletal MuscleIncludes drugs such as Carisoprodol, Chlorphenesin Relaxants Carbamate,Chlorzoxazone, and Cyclobenzaprine HCl Therapeutic Electrolytes/MineralsNutrients/Minerals/ Electrolytes Vitamins Toxicologic Agents OpioidAntagonists

In some embodiments, the active agent may be an immunogenic composition,such as, but not limited to, an antigen, an epitope, a T cell, a B cell,combinations thereof, and the like. An antigen may be a polypeptideantigen or a non-amino acid antigen. In some embodiments, the antigencan be a microbial antigen (e.g., a bacterial, viral, fungal, orparasitic antigen), a tumor antigen, or other antigens which are ofinterest for administration to a subject (e.g., by delivery of theantigen to the mucosal immune system as described herein) to elicit animmune response in the subject. Also of interest is modification ofantigens that are useful in eliciting antibodies which can betherapeutically beneficial to the subject. In some instances, theantigen may be a tumor antigen (e.g., a fragment of a tumor from thesubject) that is delivered to the mucosal immune system in the subjectusing the active agent delivery devices described herein in order toelicit an immune response (e.g., an increase in production of anti-tumorantibodies) that targets the tumor in the subject.

The active agent of the present disclosure can be formulated in avariety of different ways in an active agent formulation. In general,the active agent is formulated in a manner compatible with the activeagent, the condition to be treated, and the route of administration tobe used. The active agent can be provided in any suitable form, e.g., inthe form of a pharmaceutically acceptable salt, and can be formulated tobe suitable for administration into and/or through a mucosal membrane ina subject. Where the active agent is provided as a liquid formulation,the active agent can be provided as a ready-to-use dosage form that iscontained in the active agent reservoir of the active agent deliverydevice. Methods for formulating active agents can be adapted from thoseavailable in the art. For example, an active agent can be provided in apharmaceutical formulation that includes a therapeutically effectiveamount of the active agent and a pharmaceutically acceptable carrier(e.g., saline). The pharmaceutical formulation may optionally includeother additives (e.g., buffers, stabilizers, preservatives, and thelike). In some embodiments, the formulations are suitable foradministration to a mammal, such as those that are suitable foradministration to a human.

Methods

Aspects of embodiments of the present disclosure further include methodsof using the devices, e.g., to deliver an active agent to a subject.Generally, methods of the present disclosure will include administeringone or more active agents to a subject, for example by administering anactive agent delivery device described herein to the subject. Variousforms of administration are possible, depending on the target mucosaltissue. For example, the device may be administered to the subject byhaving the subject ingest the active agent delivery device (e.g., fordelivery of an active agent to the stomach, intestine, etc.). In otherembodiments, the active agent delivery device may be applied to amucosal surface in the subject. For example, the active agent deliverydevice can be applied to the mucosal surface in the subject with theactive agent delivery nozzle of the device facing the mucosal surface(e.g., for delivery of an active agent to a buccal or nasal mucosalsurface).

As described above, the active agent delivery device may beself-contained, such that the power reservoir is activated by contactingthe device with the appropriate conditions within the subject, such aspH, temperature, aqueous medium, etc. In other embodiments, the activeagent delivery device may be activated prior to administration to thesubject. For example, as shown in FIG. 4 and described herein, anaqueous medium reservoir can be provided as a separate element from theactive agent delivery device. The aqueous medium reservoir can beattached to the active agent delivery device around the power reservoirend of the device, such that a frangible wall of the aqueous mediumreservoir is broken and an aqueous medium is released from the aqueousmedium reservoir. As described above, contacting the exterior surface ofthe power reservoir with the aqueous medium can facilitate thedissolution and/or degradation of the dissolvable/degradable surface ofthe power reservoir, and thus allow the aqueous medium to contact thecontents of the power reservoir.

In other embodiments, the aqueous medium can be contained in an aqueousmedium reservoir in the active agent delivery device. For example, asshown in FIG. 11, the aqueous medium reservoir can be positioned in thedevice adjacent to the power reservoir with a frangible separatorpositioned between the power reservoir and the aqueous medium reservoir.In these embodiments, activation of the active agent delivery device caninclude puncturing and/or breaking the frangible separator between thepower reservoir and the aqueous medium reservoir, such that an aqueousmedium contained in the aqueous medium reservoir contacts the contents(e.g., a pressure generating material, such a gas generating material)of the power reservoir, thus activating the contents of the powerreservoir.

The dosages may be administered to a variety of different types ofsubjects. The subject to be treated can be one that is in need oftherapy, where the subject to be treated is one amenable to treatmentusing the active agent. Accordingly, a variety of subjects may beamenable to treatment using the active agents disclosed herein.Generally, such subjects are “mammals”, with humans being of interest.Other subjects can include domestic pets (e.g., dogs and cats),livestock (e.g., cows, pigs, goats, horses, and the like), rodents(e.g., mice, guinea pigs, and rats, e.g., as in animal models ofdisease), as well as non-human primates (e.g., chimpanzees, andmonkeys).

The active agents delivered using the active agent delivery devicesdisclosed herein find use in treatment of a condition or disease in asubject that is amenable to treatment by administration of the activeagent. By “treatment” is meant that at least an amelioration of thesymptoms associated with the condition afflicting the subject isachieved, where amelioration is used in a broad sense to refer to atleast a reduction in the magnitude of a parameter, e.g., symptom,associated with the condition being treated. As such, treatment alsoincludes situations where the pathological condition, or at leastsymptoms associated therewith, are completely inhibited, e.g., preventedfrom happening, or stopped, e.g. terminated, such that the host nolonger suffers from the condition, or at least the symptoms thatcharacterize the condition. Thus, treatment includes: (i) prevention,that is, reducing the risk of development of clinical symptoms,including causing the clinical symptoms not to develop, e.g., preventingdisease progression to a harmful state; (ii) inhibition, that is,arresting the development or further development of clinical symptoms,e.g., mitigating or completely inhibiting an active disease; and/or(iii) relief, that is, causing the regression of clinical symptoms.

The amount of active agent administered can be initially determinedbased on guidance of a dose and/or dosage regimen of the parent drug. Insome instances, the active agent delivery devices of the presentdisclosure can provide for targeted delivery, thus providing for atleast one of reduced dose or reduced administrations in a dosageregimen. Thus, the active agent delivery devices can provide for reduceddose and/or reduced administration in a dosage regimen relative to theparent drug prior administered by a different means (e.g., oral dosageformulation).

In some embodiments, multiple doses of an active agent are administered.The frequency of administration of the active agent can vary dependingon any of a variety of factors, e.g., severity of the symptoms,condition of the subject, etc. For example, in some embodiments, anactive agent is administered once per month, twice per month, threetimes per month, every other week (qow), once per week (qw), twice perweek (biw), three times per week (tiw), four times per week, five timesper week, six times per week, every other day (qod), daily (qd), twice aday (qid), or three times a day (tid).

Kits

Aspects of the present disclosure additionally include kits that includean active agent delivery device as described in detail herein. In someinstances, the kit includes a packaging for containing the active agentdelivery device. The packaging may be a sealed packaging, e.g., in awater vapor-resistant container, optionally under an air-tight and/orvacuum seal. In certain instances, the packaging is a sterile packaging,configured to maintain the device enclosed in the packaging in a sterileenvironment. By “sterile” is meant that there are substantially nomicrobes (such as fungi, bacteria, viruses, spore forms, etc.). The kitsmay further include additional active agent delivery devices, such astwo or more active agent delivery devices, which can be packed togetheror individually.

Also provided are containers, which may be sealed, e.g., with aresealable cap, that include one or more of the devices. The containermay be sold in a kit form, e.g., with associated packaging.

In certain embodiments, the kit includes a second active agentformulation. The second active agent formulation can include, forexample, a mucosal treatment agent that may be used to modify a mucosallayer in a subject. The mucosal treatment agent can, for instance,modify a physical property of the mucosal layer, such as, but notlimited to, increasing permeability of the mucosal layer to activeagent, increasing active agent absorption into the mucosal layer, andthe like. In some cases, the mucosal treatment agent is a pre-treatmentagent. By pre-treatment agent is meant that the mucosal treatment agentis administered prior to administration of the active agent deliverydevice to the subject. In other instances, the mucosal treatment agentmay be administered substantially simultaneously with the agent deliverydevice. In yet other instances, the mucosal treatment agent is apost-treatment agent, where the mucosal treatment agent is administeredto the subject after the agent delivery device is administered to thesubject. Combinations of the above described treatment regimens may alsobe used.

In addition to the above components, the subject kits may furtherinclude instructions for practicing the subject methods. Theseinstructions may be present in the subject kits in a variety of forms,one or more of which may be present in the kit. One form in which theseinstructions may be present is as printed information on a suitablemedium or substrate, e.g., a piece or pieces of paper on which theinformation is printed, in the packaging of the kit, in a packageinsert, etc. Another means would be a computer readable medium, e.g.,CD, DVD, Blu-Ray, computer-readable memory, etc., on which theinformation has been recorded or stored. Yet another form is a websiteaddress which may be used via the Internet to access the information ata removed site. Any convenient form of instructions may be present inthe kits.

As can be appreciated from the disclosure provided above, embodiments ofthe present invention have a wide variety of applications. Accordingly,the examples presented herein are offered for illustration purposes andare not intended to be construed as a limitation on the invention in anyway. Those of ordinary skill in the art will readily recognize a varietyof noncritical parameters that could be changed or modified to yieldessentially similar results. Thus, the following examples are put forthso as to provide those of ordinary skill in the art with a completedisclosure and description of how to make and use the present invention,and are not intended to limit the scope of what the inventors regard astheir invention nor are they intended to represent that the experimentsbelow are all or the only experiments performed. Efforts have been madeto ensure accuracy with respect to numbers used (e.g. amounts,temperature, etc.) but some experimental errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by mass,molecular mass is mass average molecular mass, temperature is in degreesCelsius, and pressure is at or near atmospheric.

EXAMPLES Example I. Device Activated by pH

A schematic of an active agent delivery device 100 is shown in FIG. 1,where the active agent delivery device is activated by pH. As shown inFIG. 1, panel A, the active agent delivery device 100 includes tworeservoirs, the power reservoir 101 and the active agent reservoir 102,separated by a movable separator (i.e., a movable piston) 103. The powerreservoir 101 contains a mixture of chemicals (citric acid and sodiumbicarbonate) in a powder form. As shown in FIG. 1, panel D, the activeagent delivery device 100 is administered to a subject orally. Uponarrival at the intestinal site, the active agent delivery device 100 isactivated and CO₂ is generated inside the power reservoir 101, whichincreases the pressure inside the power reservoir 101. Activation of thecontents of the power reservoir 101 occurs when the aqueous medium atthe intestinal site enters into the power reservoir through one or morevalves 105 in the power reservoir 101. Each valve 105 includes a holethe wall of the power reservoir 101, and also includes a pH sensitivematerial (not pictured). Upon contact of the pH sensitive material withthe relatively higher pH in the intestinal site (e.g., as compared tothe stomach) the pH sensitive material can degrade, thus opening thehole in the wall of the power reservoir for entry of the surroundingaqueous medium into the power reservoir 101. As shown in FIG. 1, panelB, the increase in pressure exerts a force on the piston 103, whichmoves the piston 103 into the active agent reservoir 102 and the activeagent solution is then ejected from the nozzle 104 with high velocity.

FIG. 1, panel C, shows images of an active agent delivery device overtime, where the active agent delivery device was activated and thenejected the contents of the active agent reservoir from the nozzle withhigh velocity.

Example II. Device Activated by Temperature and pH

A schematic of an active agent delivery device 200 and its ejectionmechanism is shown in FIG. 2, where the active agent delivery device isactivated by temperature and pH. FIG. 2, panel A, shows a side view ofthe device. As shown in FIG. 2, panel B, the interior of the activeagent delivery device 200 includes two reservoirs separated by a movablepiston 203. The power reservoir 201 contains a liquid with avaporization temperature of 40° C. The active agent reservoir 202contains an active agent and is sealed at one end by a freely movableguided piston 203 that separates the active agent reservoir 202 from thepower reservoir 201 and has a delivery nozzle 204 at the other end thatis sealed with a pH responsive polymer to maintain the active agentintegrity. The nozzle 204 will open at an intestinal site by dissolutionof the pH responsive polymer at the relatively higher pH of theintestinal site (e.g., as compared to the stomach). Exterior to thepower reservoir 201 of the active agent delivery device 200 is a heatreservoir 203, which contains food grade (94%-97%) anhydrous calciumchloride. The amount of anhydrous calcium chloride used is negligible ascompared to the reported oral toxicity levels (e.g., oral dose of morethan 2000 mg/kg is reported in the Material Safety Data Sheet forcalcium chloride). The heat reservoir 203 has valves (e.g., holes) 205on the outer wall, which are sealed with a pH responsive polymer andprevent the surrounding aqueous medium (e.g., water) from entering theheat reservoir 203 prior to the arrival of the active agent deliverydevice 200 to its target site (e.g., buccal or intestinal). Once the pHresponsive valves 205 are dissolved at the target site, water from theoral cavity or intestine enters the heat reservoir 203. Water andanhydrous calcium chloride are brought into contact in the heatreservoir 203 and the heat that evolves from the dissolution of thecalcium chloride heats the interior of the device, and thus heats thecontents of the power reservoir 201. As a result of the rise intemperature (e.g., from 37° C. to 40° C.), the fluid mixture in thepower reservoir 201 vaporizes and the hydraulic pressure on one side ofthe piston 206 increases. As shown in FIG. 2, panel C, the rise inpressure exerts a force on the piston 206, which moves the piston 206 inthe manner of a plunger into the active agent reservoir 202 and theactive agent formulation is then ejected from the nozzle 204 with highvelocity. The active agent ejection power and velocity can be controlledby the amount of chemicals inside the power reservoir 201.

Example III. Device Activated by pH

A schematic of an active agent delivery device 300 and its ejectionmechanism is shown in FIG. 3. As shown in FIG. 3, panel A, the interiorof the device 300 includes a movable piston 301 filled with a mixture oftwo chemicals (e.g., citric acid and sodium bicarbonate) in a powderform (e.g., the movable piston includes the power reservoir). The activeagent reservoir 302 contains an active agent formulation and is sealedat one end by a freely movable guided piston 301 that separates theactive agent reservoir 302 from the active agent formulation containedin the piston 301 and has a delivery nozzle 303 at the other end that issealed with a pH responsive polymer to maintain the active agentintegrity. The nozzle 303 will open at the target site by dissolution ofthe pH responsive polymer. The device 300 also includes a top reservoir304 around the top portion of the piston 301 that contains pores on theouter wall, which are sealed with pH responsive polymer and preventwater from entering the top reservoir 304 of the device 300 prior to itsarrival to the target site. Water and the contents of the piston 301 arebrought into contact at the target site (e.g., the pH responsive polymeris designed to dissolve at the target site in response to the pH at thetarget site), which results in a chemical reaction and generation ofcarbon dioxide which increases the pressure inside the piston 301. Asshown in FIG. 3, panel B, after administration of the device 300 andupon arrival at the target site, the pH responsive polymer covering thepores of the device's exterior dissolve, allowing the surroundingaqueous medium to enter the top reservoir 304. As shown in FIG. 3, panelC and panel D, carbon dioxide is generated when the aqueous mediumcontacts the contents of the piston 301, which exerts a hydraulicpressure on one side of the piston 301 and moves the piston 301 in themanner of a plunger into the active agent reservoir 302 and the activeagent formulation in the active agent reservoir 301 is then ejected fromthe nozzle 303 with high velocity. The active agent ejection power andvelocity can be controlled by the amount of chemicals inside the piston301.

Example IV. Device Configured to have a Desired Active Agent ReleaseTime

A schematic of an active agent delivery device 400 and its ejectionmechanism is shown in FIG. 4. As shown in FIG. 4, panel A, the interiorcompartment of the device 400 includes two reservoirs separated by amembrane 409 and a movable piston 401. The active agent reservoir 402 isa sterile container that contains an active agent formulation and has asealed delivery nozzle 403. The power reservoir 404 contains a drymixture of citric acid and sodium bicarbonate which is sealed at one endby a separating region from the active agent reservoir 402 and is sealedwith a pH responsive polymeric valve 405 at the other end. The pHresponsive polymeric valve 405 can be designed to dissolve at a desiredtime (e.g., time, T) after exposure to a known amount of water (X amountof water or other solvent for the polymeric valve 405). The exteriorcompartment 406 of the device 400 includes a reservoir 407 filled with Xamount of water (or other solvent) and is sealed with a thin membrane408. As shown in FIG. 4, panel B, prior to administration of the deviceto the subject, the interior and the exterior compartments are attachedtogether. This results in breakage of the thin membrane 408 sealing ofthe exterior compartment 407 and exposes the power reservoir 404 of theinterior compartment to water. The polymeric valve 405 of the powerreservoir 404 dissolves and after T time, allowing the dry power mixtureinside the power reservoir 404 to absorb the water and trigger achemical reaction, which generates a volume of CO₂ as a product. Thehydraulic pressure increases inside the device, which breaks theseparating membrane 409, and exerts a force on the piston 401, whichmoves the piston 401 in the manner of a plunger into the active agentreservoir 402, which will break a seal 410 on the nozzle 403 and theactive agent formulation is then ejected from the nozzle 403 with highpressure.

Experiments were performed utilizing an active agent delivery device ofthe present Example. The active agent delivery device included apolymeric valve surrounding a portion of the power reservoir (see, e.g.,polymeric valve 405 illustrated in FIG. 4), which was a polymer designedto degrade after exposure to water after a desired amount of time (e.g.,about 1 min, about 25 min, and about 2 hours and 30 min). The activeagent delivery device was loaded with a hydrophilic dye in the activeagent reservoir (e.g., to simulate an active agent formulation). Theactive agent delivery device and the exterior compartment were attachedtogether and the activation time was recorded. FIG. 13A shows aphotograph of an active agent delivery device 38 second afteractivation, which indicates activation in 38 second and complete releaseof the dye in less than 1 second. FIG. 13B shows photographs of adifferent device at various time points, which indicated activation atabout 23 minutes. FIG. 13C shows photographs of a different device atvarious time points, which indicated activation at about 2 hr and 30 min(e.g., 2 hr 38 min). In all examples shown in FIGS. 13A-13C, the activeagent formulation (e.g., dye) was released in less than 1 second. Anactive agent delivery device that releases the active agent formulationafter a certain desired time period may facilitate a delayed release ofthe active agent formulation, such as a delayed release of the activeagent formulation in an intestine of a subject at a certain desired timeperiod after administration of the active agent delivery device to thesubject.

Example V. Simulation Study to Evaluate the Effect of Pressure onPenetration Depth Through the Intestinal Wall

Simulation results are shown in FIGS. 5A and 5B. The simulation wasperformed in ANSYS Fluent 15.0 using a 2D axisymmetric model with atransient (timestep of 10⁻⁴ s) pressure-based solver. An implicit volumeof fluid model was used for multiphase modeling, and laminar flow wasassumed. Three phases were modeled: chyme, mucus (with identicalmechanical properties, modeled as different phases for visualizationpurposes), and active agent (modeled with the mechanical properties ofwater). Diffusion of active agent was ignored, which was justified dueto the very high Peclet number of the system (˜10⁷, using Pe=UL/D withL=200 um, U=5 m/s from simulation, and D on the order of 10⁻⁶ cm²/s).The mucus and chyme were modeled as non-Newtonian power law fluids,according to the equation:

η=k{dot over (γ)} ^(n-1)

where the consistency index k=1.412 kg-s^(n-2)/m, the power-law indexn=0.15, is the shear rate and is the viscosity. A maximum viscositylimit of 10 kg/m-s was used to prevent solution divergence in areas withzero shear rate. These parameters were taken from Cone (2009).

The mucus layer was assumed to be 200 μm thick based on publishedmeasurements of gastrointestinal mucus thickness (Atuma et al., 2001). Apressure boundary condition 1 cm away from the wall and 250 μm indiameter was used to simulate the ejection of the active agent from thedevice. Pressure data was taken from experiments and was curve fit usinga 6^(th)-order polynomial fit in Microsoft Excel. The maximum pressurewas 133 kPa, which decayed to ambient pressure (100 kPa). This was inputas a time-dependent pressure boundary condition using an interpreted UDFwritten in C.

A number of simplifying assumptions were made in designing this model.The walls of the intestine were treated as rigid, immobile, and flatsurfaces, ignoring the peristaltic motion of the intestine, thedeformability of the intestinal wall, and the intestinal wallmicrostructure. Bulk flow in the intestine, which would occur in thedirection perpendicular to the jet of released active agent, was alsoignored. These assumptions were reasonable in light of the very shorttimescale of the active agent jet (reaching the wall within 5milliseconds) and the comparatively small size of the microvilli whencompared to the mucus layer. A simplified mechanical model of mucus andchyme was used, treating both as shear-thinning fluids rather thanviscoelastic and spatially heterogeneous materials.

Simulations indicated that rapid, complete penetration of the mucuslayer can occur within 5 ms (see FIG. 5A), even from 1 cm away from thewall (roughly half-way across the lumen of a typical human smallintestine) with an overpressure at the device outlet of 33 kPa, whichwas attained using the devices of the present disclosure.

The pressure at the wall opposite the active agent jet origin reached 31kPa overpressure within 3 ms (see FIG. 5B), demonstrating that littleloss of pressure occurred during active agent jet penetration of themucus layer. It has been shown that even small hydrodynamic pressureincreases (on the order of hPa) enhance the permeability of endothelialcell layers (Tokuda, 2009), which should enhance absorption of activeagent by the endothelium of the small intestine.

Calculation of wall shear stresses from the surface strain ratesaccording to the shear stress equation for a power-law fluid gave wallshear stresses on the order of 10 Pa, which was well withinphysiological tolerances. The results indicated that the active agentdelivery devices are safe to use without causing significant damage tothe epithelium.

Example VI. In Vitro Delivery of Ovalbumin Across Pig Intestinal Tissue

The amount of ovalbumin delivered across intestinal tissue with andwithout using an active agent delivery device of the present disclosureis shown in FIG. 6.

For these studies, the lower wells of a Boyden chamber were filled with3 mL of phosphate buffered saline (PBS) medium, millipore filters (poresize 0.2 μm) were inserted, and the whole assembly was placed onto a hotplate at 37° C. This was done to equilibrate the temperature of themucosa slices and the chamber. Intestinal tissue was obtained fromslaughtered domestic pigs. The tissue was kept in ice until isolationwas done with a scalpel to an average thickness of 500±110 μm (n=3).Within 2 hrs of slaughter, the intestinal lumen was cut and the tissuewas mounted on top of the filter with a forceps. The tissue covered theentire surface of the filter. 3 mL of medium at 37° C. was added to theupper well. The active agent delivery device was loaded with 400 μg ofAlexa Fluor Ovalbumin (ovalbumin conjugated with fluorescent label) in100 μL PBS, was held close to the intestinal tissue in the upper welland activated atop of the inner lumen of the small intestine in theupper chamber. For the control study, the same amount of Alexa FluorOvalbumin (400 μg in 100 μL) was deposited into the upper chamber usinga dropper). 50 μL of solution from the lower well was collected every 15minutes to study the kinetics of Ova-Alexa delivery across intestinalmembrane. For the control study, the same amount of Ova-Alexa was placedatop intestinal tissue utilizing a dropper (FIG. 6). As indicated inFIG. 6, the active agent delivery device enhanced intestinal absorptionof ovalbumin as compared to diffusion only.

Example VII. In Vitro Delivery of Ovalbumin Across Pig's Buccal MembraneTissue

The amount of ovalbumin delivered across buccal tissue with and withoututilizing an active agent delivery device of the present disclosure isshown in FIG. 7.

For these studies, the lower wells of a Boyden chamber were filled with3 mL of PBS medium, millipore filters (pore size 0.2 μm) were inserted,and the whole assembly was placed onto a hot plate at 37° C. This wasdone to equilibrate the temperature of the mucosa slices and thechamber. buccal tissue (cheeks) was obtained from slaughtered domesticpigs. The tissue was kept in ice until isolation was done with a scalpelto obtain buccal tissue (average thickness of 500±110 μm) (n=3). Within2 hrs of slaughter, the tissue was mounted on top of the filter with aforceps. The tissue covered the entire surface of the filter. 3 mL ofmedium at 37° C. was added to the upper well. The active agent deliverydevice was loaded with 400 μg of Alexa Fluor Ovalbumin (ovalbuminconjugated with fluorescent label) in 100 μL PBS, was held close to thebuccal tissue in the upper well and activated in the upper chamber. Forthe control study, the same amount of Alexa Fluor Ovalbumin (400 μg in100 μL) was deposited into the upper chamber using a dropper. 50 μL ofsolution from the lower well was collected every 15 minutes to study thekinetics of Ova-Alexa delivery across buccal membrane. For the controlstudy, the same amount of Ova-Alexa was placed atop intestinal tissueutilizing a dropper (FIG. 7). As indicated in FIG. 7, the active agentdelivery device (pressure-based delivery) enhanced buccal absorption ofovalbumin as compared to diffusion only.

Example VIII. In-Vivo Buccal Delivery of Ovalbumin for Oral VaccinationUsing a Device of Example IV

Antibody response after buccal vaccination using an active agentdelivery device of the present disclosure loaded with ovalbumin. Rabbitswere immunized two times (week 0 and after blood collection at week 4)by placing the device inside the rabbits cheeks and against the buccaltissue. Serum was collected on weeks 0, 1, 2, 3, 4, 5 and 6. For tissueIgG analysis, mucosal tissue (buccal tissue, lymph nodes and payer'spatches) were collected after the animals were euthanized at week 6 forIgA analysis. ELISA results were reported as optical density (OD) at 450nm (see FIGS. 8A and 8B).

All procedures were conducted in accordance with protocols approved bythe University of California Berkeley Committee on Animal Care.Ovalbumin was chosen as a model biologic vaccine because large proteinssuch as ovalbumin have negligible oral bioavailability and ovalbumin isa common vaccine model. In vivo rabbit studies were performed on six NewZealand white rabbits weighing approximately 2.5-3.5 kg. Prior to theprocedures, the animals were sedated for calm and comfort withsubcutaneous administration of 1 mg/kg acepromazine for animal sedationand comfort. After sedation, for experimental studies, the active agentdelivery device was loaded with a solution of ovalbumin (100 μg/Kg) andwas held against the buccal tissue using a pill holder. Prior to deviceadministration, 200 μL of blood samples were taken from marginal earvein to quantify the animal's starting blood-anti-ova immunoglobulin G(IgG) levels. After device activation (time=˜1-2 min) and ovalbumindelivery the device was removed from the oral cavity. The rabbits werethen placed back in the cage. Blood samples were then taken weekly for 6weeks. Plasma was separated by centrifugation and was stored at 80° C.until analyzed. At week 4, a booster dose of 100 m/kg ovalbumin insterile PBS was given to rabbits using a similar method. Control rabbitsreceived the same amount of ovalbumin using a dropper against the buccaltissue. To evaluate the levels of anti-ovalbumin IgG antibodies, ELISAwas performed on blood serum. To evaluate anti-ovalbumin IgA antibodies(mucosal IgA) analysis 100 mg tissue was rinsed with 1×PBS, homogenizedin 1 mL of 1×PBS and stored overnight at −20° C. After two freeze-thawcycles were performed to break the cell membranes, the homogenates werecentrifuged for 5 minutes at 5000×g. The supernate was removedimmediately and ELISA was performed to monitor IgA levels in buccaltissue, payer's patches and lymph nodes.

Control rabbits received the same amount of ovalbumin using a dropperagainst the buccal tissue.

FIG. 8A provides a graph of the in vivo results from New Zealand whiterabbit buccal vaccination against ovalbumin (OVA) with and without usinga device of Example IV above. As shown in FIG. 8A, there was nosignificant antibody serum response after the control vaccination (i.e.,without using an active agent delivery device). However, vaccinationusing an active agent delivery device produced a significant serumantibody response.

FIG. 8B provides a graph of the in vivo results from New Zealand whiterabbit buccal vaccination against ovalbumin (OVA) with and without usinga device of the present disclosure. The graph in FIG. 8B shows thetissue anti-OVA IgA level. As shown in FIG. 8B, the antibody responsesin the lymph node, payer's patch and buccal tissues were significantlyhigher after vaccination using the active agent delivery device ascompared to the control.

The results for the experiments indicated that device (pressure-based)delivery to the buccal area was able to activate the immune responseeffectively without the need for adjuvant. In addition, the productionof Ova-specific IgA antibody in mucosal tissues and payer's patchesindicated that device delivery to buccal area was superior to theintramuscular route by inducing mucosal immunity.

Example IX. Device Activated by pH

A schematic of an active agent delivery device 900 is shown in FIG. 9,where the active agent delivery device is activated by pH. As shown inFIG. 9, panel A, the active agent delivery device 900 includes tworeservoirs, the power reservoir 901 and the active agent reservoir 902,separated by a movable separator (i.e., a movable piston) 903. The powerreservoir 901 contains a mixture of chemicals (citric acid and sodiumbicarbonate) in a powder form and is also separated from the activeagent reservoir by a membrane 906. The active agent delivery device 900is administered to a subject orally. Upon arrival at the intestinalsite, the active agent delivery device 900 is activated and CO₂ isgenerated inside the power reservoir 901, which increases the pressureinside the power reservoir 901. Activation of the contents of the powerreservoir 901 occurs when the aqueous medium at the intestinal siteenters into the power reservoir 901 through one or more valves 905 inthe power reservoir 901. Each valve 905 includes a hole the wall of thepower reservoir 901, and also includes a pH sensitive material. Uponcontact of the pH sensitive material with the relatively higher pH inthe intestinal site (e.g., as compared to the stomach) the pH sensitivematerial can degrade, thus opening the hole in the wall of the powerreservoir for entry of the surrounding aqueous medium into the powerreservoir 901. As shown in FIG. 9, panel B, the increase in pressureexerts a force on the piston 903, which moves the piston 903 into theactive agent reservoir 902, which will break a seal 907 on the nozzle904 and the active agent solution is then ejected from the nozzle 904with high velocity.

Example X. Device Activated by Temperature and pH

A schematic of an active agent delivery device 1000 and its ejectionmechanism is shown in FIG. 10, where the active agent delivery device isactivated by temperature and pH. As shown in FIG. 10, panel A, theinterior of the active agent delivery device 1000 includes tworeservoirs separated by a movable piston 1001. The power reservoir 1002contains a liquid with a vaporization temperature greater than normalbody temperature (e.g., 40° C.). The active agent reservoir 1003contains an active agent and is sealed at one end by a freely movableguided piston 1001 that separates the active agent reservoir 1003 fromthe power reservoir 1002 and has a delivery nozzle 1004 at the other endthat is sealed with a pH responsive polymer 1005 to maintain the activeagent integrity. The nozzle 1004 will open at an intestinal site bydissolution of the pH responsive polymer 1005 at the relatively higherpH of the intestinal site (e.g., as compared to the stomach). Exteriorto the power reservoir 1002 of the active agent delivery device 1000 isa heat reservoir 1006, which contains a composition that can generateheat upon contact with an aqueous medium (e.g., anhydrous calciumchloride). The heat reservoir 1006 has valves (e.g., holes) 1007 on theouter wall, which are sealed with a pH responsive polymer and preventthe surrounding aqueous medium (e.g., water) from entering the heatreservoir 1006 prior to the arrival of the active agent delivery device1000 to its target site (e.g., intestinal). Once the pH responsivevalves 1007 are dissolved at the target site, the surrounding aqueousmedium (e.g., water) from the intestine enters the heat reservoir 1006,thus causing the heat generating material in the heat reservoir 1006 togenerate heat, which in turn heats the contents of the power reservoir1002. As a result of the rise in temperature (e.g., from 37° C. to 40°C.), the fluid mixture in the power reservoir 1002 vaporizes and thehydraulic pressure on one side of the piston 1001 increases. As shown inFIG. 10, panel B, the rise in pressure exerts a force on the piston1001, which moves the piston 206 in the manner of a plunger into theactive agent reservoir 202 and the active agent formulation is thenejected from the nozzle 1004 with high velocity.

Example XI. Self-Contained Device

A schematic of a self-contained active agent delivery device 1100 andits ejection mechanism is shown in FIG. 11. As shown in FIG. 11, panelA, the interior compartment of the device 1100 includes a powerreservoir 1004 and an active agent reservoir 1102 separated by amembrane 1109 and a movable piston 1101. The active agent reservoir 1102is a sterile container that contains an active agent formulation and hasone or more sealed delivery nozzles 1103. The power reservoir 1104contains a pressure generating material (e.g., a gas generatingmaterial, such as a dry mixture of citric acid and sodium bicarbonate),which is sealed at one end by membrane 1109 from the active agentreservoir 1102 and is sealed with a frangible valve 1105 at the otherend. The device 1100 also includes an aqueous medium reservoir 1107filled with an aqueous medium. As shown in FIG. 11, panel B, during useof the device, a plunger 1108 attached to one or more puncturingelements 1110 can be depressed, which results in breakage of thefrangible valve 1105 sealing the aqueous medium reservoir 1107 and thusexposes the power reservoir 1104 to the aqueous medium contained in theaqueous medium reservoir 1107. This allows the gas generating materialinside the power reservoir 1104 to activate and trigger a chemicalreaction, which generates a volume of gas as a product. The hydraulicpressure increases inside the device, which exerts a force on the piston1101, which moves the piston 1101 in the manner of a plunger into theactive agent reservoir 1012, which will break a seal 1111 on the nozzle1103 and the active agent formulation is then ejected from the nozzle1103 with high pressure.

FIG. 11, panel C shows an alternative embodiment of an active agentdelivery device, where the nozzle 1150 extends from a side wall of theactive agent reservoir 1151. A nozzle that extends from a side wall ofthe device (e.g., extend from a side wall of the active agent reservoir)can facilitate delivery of the active agent to a mucosal layerpositioned alongside of the device, such as in a nasal cavity.

Example XII. Low-Profile Device

A schematic of a low-profile active agent delivery device 1200 is shownin FIG. 12. As shown in FIG. 12, panel A, the active agent deliverydevice 1200 includes two reservoirs, the power reservoir 1201 and theactive agent reservoir 1202, separated by a gap (e.g., air space) 1203.The power reservoir 1201 contains a pressure generating material (e.g.,a gas generating material) and is separated from the active agentreservoir by one or more membranes 1206. The low-profile active agentdelivery device 1200 can be applied to a mucosal surface in a subject,such as applied to a buccal surface. Activation of the contents of thepower reservoir 1201 occurs, for example when an aqueous medium at theadministration site enters into the power reservoir 1201 through one ormore valves 1205 in the power reservoir 1201. Each valve 1205 includes ahole the wall of the power reservoir 1201, and also includes adissolvable material. Upon application to the mucosal surface, thedissolvable material can degrade, thus opening the valve 1205 of thepower reservoir for entry of the surrounding aqueous medium into thepower reservoir 1201. As shown in FIG. 12, panel B, an increase inpressure in the power reservoir 1201 due to activation of the pressuregenerating material exerts a force on the active agent reservoir 1202,which will break a seal 1207 on the nozzle 1204 and the active agentsolution is then ejected from the nozzle 1204 with high velocity.

FIG. 12, panel C shows an alternative embodiment of a low-profile activeagent delivery device, where the nozzles 1250 protrude from a surface ofthe active agent reservoir 1251. The nozzles can have a shape of a coneor frustum, and can facilitate delivery of the active agent into and/orthrough a mucosal layer upon which the device is applied.

The preceding merely illustrates the principles of the invention. Itwill be appreciated that those skilled in the art will be able to devisevarious arrangements which, although not explicitly described or shownherein, embody the principles of the invention and are included withinits spirit and scope. Furthermore, all examples and conditional languagerecited herein are principally intended to aid the reader inunderstanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1-27. (canceled)
 28. A device, comprising: a first reservoir at a firstend of the device, the first reservoir configured to contain an activeagent formulation; a second reservoir at a second end of the device, thesecond reservoir configured to eject the active agent formulation at apressure of from 25 kPa to 150 kPa; and a moveable separator separatingthe first and second reservoirs.
 29. The device of claim 28, wherein thesecond reservoir comprises at least one valve that separates the secondreservoir from an exterior of the device.
 30. The device of claim 28,wherein the device is configured to eject the active agent formulationin 10 msec or less.
 31. The device of claim 28, wherein the device isconfigured to eject the active agent formulation at a velocity of 1 m/sor more.
 32. The device of claim 28, wherein the device comprises anozzle separating the first reservoir from the exterior of the device.33. The device of claim 28, wherein the second reservoir contains a gasgenerating material.
 34. The device of claim 33, wherein the gasgenerating material is configured to produce a gas upon contact with anaqueous medium.
 35. The device of claim 34, wherein the gas comprises aproduct of a chemical reaction.
 36. The device of claim 33, wherein thegas generating material comprises a volatile liquid.
 37. The device ofclaim 36, wherein the volatile liquid has a vaporization temperatureranging from 37.5° C. to 45° C.
 38. The device of claim 28, wherein themoveable separator comprises a gas generating material.
 39. The deviceof claim 28, further comprising a third reservoir in heat transferrelationship with the second reservoir, wherein the third reservoircomprises a heat generating material configured produce heat uponcontact with an aqueous medium.
 40. The device of claim 28, furthercomprising a third reservoir configured to contact at least a portion ofthe second end of the device and to activate the second reservoir. 41.The device of claim 40, wherein the second reservoir contains a gasgenerating material, and the third reservoir contains an aqueous medium.42. The device of claim 28, wherein the active agent comprises amacromolecule.
 43. The device of claim 42, wherein the macromoleculecomprises a protein.
 44. The device of claim 28, wherein the activeagent formulation comprises a liquid.
 45. The device of claim 28,wherein the device comprises a tubular member having a planar surface atthe first end and a hemispherical structure at the second end.
 46. Thedevice of claim 28, wherein the device is configured to promote contactof the first end with a mucosal surface in a subject.
 47. The device ofclaim 29, wherein the valve comprises an opening and a pH responsivematerial disposed in the opening.
 48. The device of claim 47, whereinthe pH responsive material comprises a polymer.
 49. The device of claim29, wherein the valve comprises a hole in a wall of the secondreservoir.
 50. The device of claim 29, wherein the valve is configuredto degrade or dissolve at a pH of 4 or less.
 51. The device of claim 29,wherein the valve is configured to degrade or dissolve at a pH of 5 ormore.
 52. The device of claim 28, wherein the second reservoir isconfigured to eject the active agent formulation at a pressure of from25 kPa to 125 kPa.
 53. The device of claim 28, wherein the secondreservoir is configured to eject the active agent formulation at apressure of from 25 kPa to 100 kPa.
 54. The device of claim 28, whereinthe second reservoir is configured to eject the active agent formulationat a pressure of from 25 kPa to 75 kPa.
 55. The device of claim 28,wherein the second reservoir is configured to eject the active agentformulation at a pressure of from 25 kPa to 50 kPa.
 56. The device ofclaim 28, wherein the second reservoir is configured to eject the activeagent formulation at a pressure of from 30 kPa to 50 kPa.
 57. The deviceof claim 29, wherein the valve comprises a pH responsive materialconfigured to degrade or dissolve to provide an inlet into the secondreservoir in response to a change in pH.
 58. A method, comprising:administering the device of claim 28 to a subject.
 59. The method ofclaim 58, further comprising using the administered device to treat adisease condition of the subject.
 60. A kit comprising: a deviceaccording to claim 28; and a packaging containing the device.
 61. Thekit of claim 60, wherein the packaging comprises at least two devicesaccording to claim
 28. 62. The kit of claim 60, further comprising amucosal treatment agent.